Direct Asymmetric Hydrogenation and Dynamic Kinetic Resolution of Aryl Ketones Catalyzed by an Iridium-NHC Exhibiting High Enantio- and Diastereoselectivity

Article abstract of DOI:10.1002/chem.201904911

A chiral iridium carbene-oxazoline catalyst is reported that is able to directly and efficiently hydrogenate a wide variety of ketones in excellent yields and good enantioselectivity (up to 93 % ee). Moreover, when using racemic α-substituted ketones, excellent diastereoselectivities were obtained (dr 99:1) by dynamic kinetic resolution of the in situ formed enolate. Overall, the herein described hydrogenation occurs under ambient conditions using low hydrogen pressures, providing a direct and atom efficient method towards chiral secondary alcohols.

Full text of DOI:10.1002/chem.201904911

A Journal of
Accepted Article
Title: Direct Asymmetric Hydrogenation and Dynamic Kinetic
Resolution of Aryl Ketones Catalyzed by an Iridium-NHC
Exhibiting High Enantio- and Diastereoselectivity
Authors: Chinna Ayya Swamy P, Adrii Varenikov, and Graham de
Ruiter
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201904911
Link to VoR: http://dx.doi.org/10.1002/chem.201904911
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10.1002/chem.201904911
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COMMUNICATION
Direct Asymmetric Hydrogenation and Dynamic Kinetic
Resolution of Aryl Ketones Catalyzed by an Iridium-NHC
Exhibiting High Enantio- and Diastereoselectivity
Chinna Ayya Swamy P,[a] Andrii Varenikov[a] and Graham de Ruiter*[a]
Abstract: Here we report a chiral iridium carbene-oxazoline catalyst
that is able to directly and efficiently hydrogenate a wide variety of
ketones in excellent yields and good enantioselectivity (up to 93% ee).
Moreover, when using racemic α-substituted ketones, excellent
diastereoselectivities were obtained (dr 99:1) via dynamic kinetic
resolution of the in-situ formed enolate. Overall, the herein described
hydrogenation occurs under ambient conditions using low hydrogen
pressures, providing a direct and atom efficient method towards chiral
secondary alcohols.
will facilitate efficient transfer of the catalyst’s chiral topology to
the pro-chiral substrate. Indeed our recently developed chiral
imidazo[1,5-a]pyridine-oxazoline ligands facilitated the rhodium
catalyzed hydrosilylation of ketones with good enantioselectivities
(up to 95% ee).[9] Encouraged by these results, we envisioned that
these ligands might also provide unprecedented reactivity in
direct asymmetric hydrogenation of aryl ketones.
OH
OH
O
H
N
HO
S
N
O
Phenylephrine
OH
Over the past few decades, N-heterocyclic carbenes (NHCs)
have established themselves as a tour de force in transition metal
catalysis.[1] Much of their accomplishments can be attributed to
several desirable properties that includes (i) their good σ-donating
capabilities resulting in strong metal-ligand bonding, which
prevents catalyst deactivation by loss of ligand, and (ii) their high
synthetic modularity resulting in tailored made NHCs with distinct
physicochemical properties.[2] The high synthetic modularity has
also resulted in the design and synthesis of chiral NHCs that have
found fruitful applications in asymmetric synthesis.[3] Some of the
most well-known structural motifs are those that contain
monodentate ligand architectures where the chirality is either
APJ Receptor Antagonist
CF3
H
N
O
NHMe
Fluoxetine
BnO
OMe
NHCHO
Formoterol
Asymmetric Hydrogenation
BArF24
R1
O
racemic
OH
[Cat]
N
N
N
C
Toluene, 0 °C
H2 (6 bar)
R
R
Ir
✔
O
COD
Enriched
Up to 93% ee
induced via the imidazolium backbone or via the nitrogen-ligated
Dynamic Kinetic Resolution ( up to 99:1 dr)
>23 Examples
R2
[Cat]
4]
substituents.[3h,
Bidentate ligands containing an NHC-
Mild Conditions (6 bar, 0 °C)
functionality and a chiral auxiliary in close proximity to the metal
center (e.g. oxazoline) have also been highly successful,[3a, 5] in
particular in the asymmetric hydrogenation of substituted
alkenes.[6] Yet, despite the remarkable progress that has been
made during the past decade, several organic transformations still
remain arduous with transition-metal NHCs. To illustrate, the
hydrogenation of polar C=X bonds (X = O or NR1) has rarely been
demonstrated, while these substrates are important precursors to
many pharmaceutically relevant molecules (Figure 1).[7] To date,
only one example has been reported for the direct asymmetric
hydrogenation of aryl ketones achieving an enantiomeric excess
(ee) of only 5% for acetophenone.[8] Although the lack of reactivity
of transition-metal NHCs in these type of transformations is not
entirely clear, it does provide strong incentives for developing new
methodologies that can facilitate efficient chirality transfer to
challenging substrates such as ketones, imines, and heterocycles.
To provide novel solutions for these challenges, we have
launched a research program, centered around developing NHCs
with chiral oxazoline auxiliaries that are in close proximity to the
metal center. We reasoned that a strategy including oxazolines
Figure 1. Representative examples of chiral pharmaceuticals obtained via
asymmetric hydrogenation. The inset shows the herein reported direct
asymmetric hydrogenation of ketones.
Here we present four new chiral iridium carbene-oxazoline
complexes (5a–5d), based on an imidazo[1,5-a]pyridine
backbone, that are capable of directly and asymmetrically
hydrogenating various ketones with good to excellent
enantioselectivities (up to 93% ee). The reaction occurs under
mild conditions (0 oC) with low hydrogen pressures (6 bar H2). In
addition, when using racemic α-substituted ketones, dynamic
kinetic resolution ensured good diastereoselectivity in several
substrates including pharmaceutically relevant sulfonamides.
Our initial investigation started with the synthesis of novel
iridium complexes (5a–5d), according to our previously reported
synthetic methodology.[9] We have updated our methodology to
include
a
salt metathesis with sodium tetrakis[3,5-
bis(trifluoromethyl)phenyl]-borate (NaBArF24), in order to increase
the solubility of our complexes in non-polar solvents (Scheme 1).
All complexes where characterized by 1H, 13C and 19F NMR
spectroscopy, and by high-resolution mass spectrometry (HRMS).
We commenced our studies by exploring the catalytic
hydrogenation of acetophenone with complexes 5a–5d. Using
catalyst 5c as archetypal example, we started with 1 mol % of
catalyst in methanol (1 mL) and 6 bar of hydrogen as the initial
catalytic conditions. Under these conditions we observed
complete conversion of acetophenone to the corresponding chiral
[a]
Dr. C. A. Swamy P, A. Varenikov and G. de Ruiter
Schulich Faculty of Chemistry
Technion – Israel Institute of Chemistry
Technion City, 3200008 Haifa, Israel
E-mail: graham@technion.ac.il
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201904911
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COMMUNICATION
alcohol with an enantiomeric excess (ee) of 51%. (Table 1, Entry
1). During these studies we used potassium tert-butoxide (KOtBu;
3 mol %) as a base to facilitate cleavage of the presumed Ir-
dihydrogen pre-catalyst. In the absence of base no reaction was
observed (Figure S189).
(Table 2; entries 6a–6j). It is evident that alkyl substituents in the
para position give the highest enantioselectivity (87–93% ee),
while the presence of electron withdrawing halides result in a
diminished enantioselectivity. (65–84% ee). Changing the
substitution pattern from para to either ortho or meta does not
affect the yield nor the enantioselectivity to a great extend (Table
2; entries 6d and 6h). Other substituents such as esters (6k),
cyano (6l), and nitro (6m) functional groups are less well tolerated
and result in diminished yields and enantioselectivities. No
reaction was observed with para-substituted alcohols and amines.
Scheme 1. Synthesis of chiral imidazo[1,5-a]pyridinium-3-ylidene iridium
complexes 5a–5d.
Cl
R1-NH2
CMEE
R1
N
N
EtOH, RT
12 h
THF, RT
18 h
NC
N
NC
N
1
CHO
N
CN
Table 1. Optimization of the reaction conditions.a
R1
2a: R1 = Mes, 81%
2b: R1 = Dipp, 91%
3a: R1 = Mes, 74%
3b: R1 = Dipp, 82%
O
OH
Catalyst (1.0 mol %), KOtBu
BArF24
HO
NH2
R2
Cl
R1
1. Ag2O
2. [IrCl(COD)]2
3. NaBArF24
(6.0 mol %), H2 (6 bar)
N
R1
N
Solvent, T, 24 h
N
N
N
DCM, RT, 18 h
eec (%)
Zn(OAc)2, Glycerol
MW, 110 °C, 30 min
Ir
Cat.
T (°C)
Solvent
Yieldb (%)
Entry
COD
O
O
N
5c
5c
5c
5c
5c
5a
5b
5d
5a
5b
5c
5d
5a
5b
5c
5d
23
23
23
23
23
23
23
23
0
0
0
0
− 20
− 20
− 20
− 20
MeOH
THF
CH2Cl2
>99
>99
>99
N/A
>99
>99
>99
>99
>99
>99
>99
>99
>99
7
51
24
20
N/A
77
41
18
49
88
77
82
86
87
50
85
85
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4a: R1 = Mes, R2 = iPr, 63%
5a: R1 = Mes, R2 = iPr, 65%
5b: R1 = Mes, R2 = tBu, 72%
5c: R1 = Dipp, R2 = iPr, 61%
R2
R2
4b: R1 = Mes, R2 = tBu, 81%
4c: R1 = Dipp, R2 = iPr, 63%
4d: R1 = Dipp, R2 = tBu, 78%
5d: R1 = Dipp, R2 = tBu, 75%
MeCN
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Encouraged by these initial results, we performed a solvent
screening study in order to establish the preferred solvent for the
hydrogenation reaction (Table 1; entry 1–5). As evident from
Table 1, good enantioselectivities (77% ee) are obtained with
toluene as solvent, without compromising on the yield (>99%).
Using toluene as solvent we evaluated the efficacy of iridium
catalysts 5a–5d in the hydrogenation of acetophenone at various
temperatures (Table 1; entry 5–16). From previous studies it is
known that the temperature can have a profound impact on the
observed enantioselectivity.[10] Our studies indicate that at room
temperature the enantioselectivity obtained with catalyst 5c is
much better than with our other iridium catalysts (Table 1; entry
5–8). However, upon reducing the temperature to 0 oC, a slight
increase in enantioselectivity was observed for 5c (Table 1; entry
11), whereas large increases were observed for catalysts 5a (88%
ee), 5b (77% ee), and 5d (86% ee). Further lowering the
temperature to −20 oC did not affect enantioselectivity to a great
extent, although yields did decrease to 30 and 7% for catalyst 5d
and 5b respectively. After optimization of the reaction conditions,
the reaction times could further be decreased to 6 hours for which
most substrates showed near to quantitative conversion (Table 2).
Using the lowest catalyst loading of 0.1 mol % did not result in an
increase in enantioselectivity nor in an increase in yield (data not
shown). However, to ensure complete conversion of all substrates
during the reaction scope (Table 2), 1.0 mol % of the catalyst was
used. The optimized conditions thus include 1.0 mol % 5a, 6.0
mol % KOtBu, 6 bar of H2, in 1.5 mL of toluene with a reaction
time of 6 h. Please note that effect of the counter ion was not
investigated in order not the impair the solubility of 5a in toluene.
The good enantioselectivity observed for the direct
asymmetric hydrogenation of acetophenone encouraged us to
further investigate the substrate scope under the optimized
reaction conditions (Table 2). These studies revealed that various
aryl ketones are well tolerated. For example, para substituted
acetophenones that bear both electron withdrawing (e.g. -F, -Cl,
>99
30
aSee supporting information for experimental details. bYields were determined
by 1H NMR spectroscopy in the presence of an internal standard. cEnantiomeric
excess (ee) for each substrate was determined by chiral HPLC and averaged
over two independent runs.
In contrast to our previously reported hydrosilylation,[9]
catalyst 5a is also able to hydrogenate quite sterically demanding
aryl ketones such as propiophenone, 2-cyclopropylphenyl ketone,
and 2,2-dimethylpropiophenone (Table 2; 6o–6q). Moreover,
under the herein reported reaction conditions ketones are
preferentially hydrogenated over alkenes (Table 2, 6r), although
α,β-substituted ketones give an intractable mixture of products.
The observed selectivity is interesting since iridium NHCs are well
known for alkene hydrogenation.[11] Notwithstanding, under the
herein reported reaction conditions alkene hydrogenation (e.g. 4-
octene or styrene) is not observed (Figure S187 and S188).
Overall, the herein reported catalysts not only show superior
enantioselectivities when compared to the only reported
hydrogenation method developed by Morris and co-workers,[8]
they also outperforms nearly all carbene-based catalyst that rely
on transfer hydrogenation.[12] Notwithstanding the results
obtained with our transition-metal NHCs, precious metal catalysts
bearing chiral phosphine ligands still report higher
enantioselectivities,[13] especially with sterically demanding
substrates such as tert-alkyl ketones.[14]
t
-Br, CF3) and electron donating (e.g. Bu, -OMe, Me) groups are
hydrogenated with reasonable to excellent enantioselectivities
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Table 2. Optimized reaction conditions and substrate scope of the direct asymmetric hydrogenation of ketones.a–d
O
OH
5a (1.0 mol %), KOtBu (6.0
mol %), H2 (6 bar)
Toluene, 0 °C, 6 h
OH
OH
OH
OH
OH
OH
OH
tBu
Me
Me
F
Cl
Br
6a, 88% ee,
99% yield
6b, 88% ee,
99% yield
6c, 93% ee,
99% yield
6d, 91% ee,
99% yield
6e, 84% ee,
66% yield
6f, 76% ee,
99% yield
6g, 79% ee,
99% yield
OH
OH
OH
OH
OH
OH
OH
EtOOC
MeO
F3C
NC
O2N
Br
6n, 84% ee,
99% yield
6h, 83% ee,
99% yield
6i, 73% ee,
99% yield
6j, 64% ee,
99% yield
6k, 40% ee,
62% yield
6l 74% ee,
55% yield
6m, 26% ee,
26% yield
OH
OH
OH
OH
6r, 11% ee,
62% yield
6q, 44% ee,
99% yield
6o, 89% ee,
99% yield
6p, 86% ee,
99% yield
aSee supporting information for experimental details. bYields were determined by 1H NMR spectroscopy in the presence of an internal standard. Isolated yields are
averaged over a series of two runs and reported in the supporting information. cEnantiomeric excess (ee) for each substrate was determined by chiral HPLC. d For
substrates 6l and 6m methanol was used as solvent.
In order to obtain mechanistic details of the hydrogenation,
we performed the reaction under the optimized reaction
conditions in the presence of 6 bar of deuterium (Figure 2 and
Figure S1–S4). In our isotope labeling experiments almost
exclusive incorporation of the isotope label was observed at the
α-position (Figure 2). In addition, according to the 1H and 13C NMR
spectra, mono-deuteration of the methyl peak is also observed,
albeit to lower extend (CH2D; ∼45%). Please note that NMR
spectra also show trace amounts of double deuteration (CHD2) of
the methyl substituent.
The observed enolization could provide further opportunities
to exploit dynamic kinetic resolution (DKR) of racemic α-
substituted ketones. Over the past decade, transition metal
catalyzed DKR has proven to be a valuable stereo-convergent
method for establishing the stereochemistry of two contiguous
stereogenic centers from racemic starting materials.[15] One of the
first examples of DKR in the direct asymmetric hydrogenation of
ketones was reported by Noyori and co-workers who
demonstrated excellent diastereoselectivity with a ruthenium
diamine-based catalyst.[16] With our iridium-NHC catalyst we were
able to obtain good diastereoselectivities (> 10:1) with various α-
substituted cyclohexanones (Table 3, 7a–7d). Extending
substrate scope to include other cyclic aromatic structures such
as α-hydroxy ketones or tetralones, resulted in significant
reduction of the observed diastereoselectivity when going from 2-
methyl-cyclohexanone (dr >10:1) to 2-methyl-tetralone (dr 3:1).
Perhaps the equilibrium between the equatorial and axial
conformers enhances the observed diastereoselectivity in
cyclohexanones, which is inhibited in tetralones. In order not to
limit these studies to relatively simple ketones, we also
investigated the activity of our iridium complex 5a in the
asymmetric hydrogenation of α-substituted β-keto sulfonamides.
The structural motifs of sulfonamides are frequently found in
pharmaceuticals with interesting biological properties (Figure 1).
To the best of our knowledge, no examples are reported for
the direct asymmetric hydrogenation of α-substituted β-keto
sulfonamides, while only three examples report on asymmetric
transfer hydrogenation.[17] We were pleased to find that under the
optimized reaction conditions our iridium complex 5a, catalyzed
the asymmetric hydrogenation of racemic α-substituted β-keto
O
HO
D
97%
5a (1.0 mol %), KOtBu (6.0
mol %), D2 (6 bar)
D
45%
Toluene, 0 °C, 9 h
Figure 2. Isotope labeling experiment upon deuteration of acetophenone with 6
bar of deuterium. Deuterium incorporation at the stereogenic carbon; > 97%; at
the methyl (∼45%)
Taking into account this information, incorporation of
deuterium into the CH3 group occurs via enolization of
acetophenone by KOtBu and subsequent protonation by
PhCD(OD)Me which builds up during the reaction. The observed
enolization of acetophenone could suggest a mechanism that
favors hydrogenation of the enolate rather than the ketone.
Although the hydrogenation of the enolate could not completely
be excluded, we believe that
a mechanism involving the
hydrogenation of the ketone is preferable since substrates lacking
any β-hydrogens are hydrogenated efficiently (Table 2, 6q), albeit
at lower enantioselectivity due the steric hindrance.
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10.1002/chem.201904911
Chemistry - A European Journal
COMMUNICATION
sulfonamides with excellent diastereoselectivities (Table 3, 7g–
7k). Changing the nature of the sulfonamide (Table 3, 7g–7i) or
the electronic nature of the phenyl substituent (Table 3, 7j–7k) did
not influence the diastereoselectivity. Please note that methanol
was used in order to increase solubility of the sulfonamide starting
materials. However, changing the nature of the solvent, did not
influence our direct hydrogenation pathway as isotope labeling
experiments showed > 80% incorporation of the deuterium label
at the carbonyl carbon (Figure S103–106).
pathway. Overall, the reaction proceeds under ambient conditions
(0 °C, 6 bar H2), with iridium complexes that contain our recently
developed chiral imidazo[1,5-a]pyridine-oxazoline NHCs. Current
efforts are directed towards obtaining mechanistic insights into
the herein reported reaction, since our catalyst lacks the
possibility to go through classical Noyori-type N–H assisted
mechanism.[18] In conclusion, this work contributes the towards
the direct asymmetric hydrogenation that proceeds in good
enantioselectivity and excellent yields. Given the modularity of the
herein present catalysts and ligands, exciting new reactions are
expected that were previously reserved for a privileged set of
phosphine-based ligands.
Table 3. Direct asymmetric hydrogenation and dynamic kinetic resolution
of α-substituted ketones.a–e
OH
O
5a (1.0 mol %), KOtBu (6.0
mol %), H2 (6 bar)
R2
R2
Acknowledgements
R1
R1
Toluene or MeOH, 0 °C, 6 h
Research was supported by the Azrieli Foundation (Israel), and
the Technion EVPR Fund – Mallat Family Research Fund. G.de.R
is an Azrieli young faculty fellow and a Horev Fellow supported by
the Taub Foundation. G.de.R wishes to thank Prof. Mark
Gandelman for the use of his chiral HPLC.
Cyclohexanones
OH
OH
OH
OH
Me
Ph
Bn
7c, dr 16:1,
19% ee, 84% yield
7b, dr >99:1,
48% ee, 99% yield
7d, dr 10:1,
15% ee, 99% yield
7a, dr >10:1,
nde, 99% yield
Keywords: Asymmetric Catalysis • Hydrogenation • N-
Others
OH
OH
Heterocyclic Carbenes • Iridium • Aryl Ketones
Me
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A. Herrmann, Angew. Chem. Int. Ed. 2002, 41, 1290-1309.
OH
7f, dr 3:1,
0% ee. 92% yield
7e, dr 5:1,
nde, 99% yield
Sulfonamides
OH
[2]
[3]
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OH
O
O
S
OH
O
S
N
O
S
Ph
Ph
N
Ph
N
O
O
Me
Me
O
Me
7g, dr >99:1,
5% ee, 99% yield
7h, dr >99:1,
35% ee, 99% yield
7i, dr >99:1,
61% ee, 99% yield
OH
O
S
OH
O
S
R1
R1
N
N
O
O
Me
O
Me
O
7k, R1= 4-OMeC6H4
dr >99:1, 18% ee, 98% yield
7j, R1= 4-FC6H4
dr >99:1, 79% ee, 95% yield
[4]
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aSee supporting information for experimental details. bYields were determined
by 1H NMR spectroscopy in the presence of an internal standard. Isolated yields
are averaged over a series of two runs. cdiastereomeric ratios were determined
by 1H NMR spectroscopy and reported in the supporting information.
dEnantiomeric excess (ee) for each substrate was determined by chiral HPLC.
eFor substrates 7a and 7e, the chiral HPLC chromatogram could not sufficiently
be resolved to determine the enantomeric excess.
[5]
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Chem. Soc. 2001, 123, 8878-8879.
In summary, we have demonstrated the asymmetric
hydrogenation of ketones that proceeds in good enantioselectivity
(up to 93% ee). Moreover, by using racemic α-substituted ketones
we were also able to obtain high diastereoselectivities via a
cascade asymmetric hydrogenation/dynamic kinetic resolution
pathway enabling the synthesis biologically relevant sulfonamides
with two contiguous stereocenters. Isotope labeling studies in
both the direct asymmetric hydrogenation as in the dynamic
kinetic resolution have unequivocally confirmed the preference of
direct asymmetric hydrogenation over a transfer hydrogenation
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10.1002/chem.201904911
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
O
Chinna Ayya Swamy P, Andrii Varenikov,
and Graham de Ruiter*
racemic
OH
[Cat]
BArF24
R1
N
Toluene, 0 °C
H2 (6 bar)
R
N
N
R
C
✔
Enriched
Ir
Up to 93% ee
Page No. – Page No.
O
COD
[Cat]
Dynamic Kinetic Resolution ( upt to 99:1 dr)
>23 Examples
R2
Direct Asymmetric Hydrogenation and
Dynamic Kinetic Resolution of Aryl
Ketones Catalyzed by an Iridium-NHC
Mild Conditions (6 bar, 0 °C)
The asymmetric hydrogenation of ketones in good enantioselectivities is reported
with a chiral Iridium-NHC catalyst. The hydrogenation occurs under mild conditions
(6 bar, 0 °C) with short reaction times (< 6 hours). In addition, when using racemic α-
substituted ketones, excellent diastereoselectivities are obtained via dynamic kinetic
resolution, which is further discussed in the herein presented research.
Exhibiting
Diastereoselectivity
High
Enantio-
and
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