Cationic NHC-Phosphine Iridium Complexes: Highly Active Catalysts for Base-Free Hydrogenation of Ketones

Article abstract of DOI:10.1002/chem.202002811

Novel bidentate N-heterocyclic carbene-phosphine iridium complexes have been synthesized and evaluated in the hydrogenation of ketones. Reported catalytic systems require base additives and, if excluded, need elevated temperature or high pressure of hydrogen gas to achieve satisfactory reactivity. The developed catalysts showed extremely high reactivity and good enantioselectivity under base-free and mild conditions. In the presence of 1 mol % catalyst under 1 bar hydrogen pressure at room temperature, hydrogenation was complete in 30 minutes giving up to 96 % ee. Again, this high reactivity was achieved in additive-free conditions. Mechanistic experiments demonstrated that balloon pressure of hydrogen was sufficient to form the activate species by reducing and eliminating the 1,5-cyclooctadiene ligand. The pre-activated catalyst was able to hydrogenate acetophenone with 89 % conversion in 5 min.

Full text of DOI:10.1002/chem.202002811

Accepted Article
Accepted Article
Title: Cationic NHC-Phosphine Iridium Complexes: Highly Active
Catalysts for Base Free Hydrogenation of Ketones
Authors: Xu Quan, Sutthichat Kerdphon, Bram B. C. Peters, Janjira
Rujirawanich, Suppachai Krajangsri, Jira Jongcharoenkamol,
and Pher G. Andersson
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0
1/2020

Chemistry - A European Journal
10.1002/chem.202002811
FULL PAPER
Cationic NHC-Phosphine Iridium Complexes: Highly Active
Catalysts for Base Free Hydrogenation of Ketones
+
[a]
+ [a]
+ [a]
[a]
Xu Quan , Sutthichat Kerdphon , Bram B. C. Peters , Janjira Rujirawanich, Suppachai
[
a]
[a]
[a][b]
Krajangsri, Jira Jongcharoenkamol and Pher G. Andersson*
[
a]
Dr. X. Quan, Dr. S. Kerdphon, B. B. C. Peters, Dr. J. Rujirawanich, Dr. S. Krajangsri, Dr. J. Jongcharoenkamol and Prof. P. G. Andersson
Department of Organic Chemistry, Stockholm University
Stockholm 10691, Sweden
E-mail: pher.andersson@su.se
[
b]
Prof. P. G. Andersson
School of Chemistry and Physics, University of Kwazulu-Natal
Private Bag X54001
Durban 4000, South Africa
+
*
X. Quan, S. Kerdphon and B. B. C. Peters contributed equally
Corresponding author
Abstract: Novel bidentate N-heterocyclic carbene-phosphine iridium
possibility to mimic phosphine ligands and numerous have
successfully found applications in transition-metal catalyzed
complexes have been synthesized and evaluated in the
hydrogenation of ketones. Reported catalytic systems require base
additives and if excluded, need elevated temperature or high
pressure of hydrogen gas to achieve satisfactory reactivity. The
developed catalysts showed extremely high reactivity and good
enantioselectivity under base-free and mild conditions. In the
presence of 1 mol% catalyst under 1 bar hydrogen pressure at room
temperature, hydrogenation was complete in 30 minutes giving up to
8
reactions.
The field of iridium-catalyzed asymmetric
hydrogenation faced an increase in the use of NHC ligands as
8c,9
well, with various successful applications being reported.
Among these, bidentate imidazolylidene-phosphine and
imidazolinylidene-phosphine ligands have been developed,
1
0
mainly for the use in olefin hydrogenation. Ketones could also
be reduced by means of ligated NHCs, however similar trends in
reaction conditions are reported compared to classical
3
d,4c,8c,11
phosphine ligands.
Namely, additives are often required
9
6% ee. Again, this high reactivity was achieved in additive-free
and if excluded, harsher conditions were applied. Herein, we
report the development of highly active bidentate NHC-
phosphine-Ir catalysts for the asymmetric hydrogenation of
ketones under neutral conditions. These catalysts require very
low H pressure and short reaction time without addition of base
2
or acid.
conditions. Mechanistic experiments demonstrated that balloon
pressure of hydrogen was sufficient to form the activate species by
reducing and eliminating the 1,5-cyclooctadiene ligand. The pre-
activated catalyst was able to hydrogenate acetophenone with 89%
conversion in 5 min.
Results and Discussion
Introduction
First, several achiral NHC-phosphine iridium complexes were
prepared and evaluated in the reduction of acetophenone 1
under different reaction conditions (Scheme 1). Under basic
Chiral alcohol motifs represent
a frequently occurring
1
functional group in natural products or their intermediates.
Among the methods to synthesize optically pure alcohols,
transition-metal catalyzed asymmetric hydrogenation of ketones
represents one of the most efficient strategy in terms of
reactivity, selectivity and atom-economy. In 1995, Noyori
t
reaction conditions (5 mol% of KO Bu), all complexes showed
good reactivity, and in most cases the reactions were complete
in 9 hours. Comparing the hydrogenation conversion in the first
hour showed that iridium catalysts Ir-F to Ir-H with
imidazolinylidene moieties were much more reactive than
catalysts Ir-A to Ir-E bearing an imidazolylidene backbone. For
example, in the first hour 54% conversion was observed with Ir-
D, while for imidazolinylidene equivalent Ir-F the reaction was
almost complete with 93% conversion. Under acidic conditions
(5 mol% of formic acid), reactions were much slower and the
catalytic activity strongly depended on the ligand structure. Over
36 hours, no conversion was observed for catalysts Ir-A to Ir-C
and Ir-E, while iridium catalysts Ir-F to Ir-H performed well and
gave 72%, 98% and 90% conversion, respectively. Next, the
iridium catalysts were tested under hydrogen pressure without
any added base or acid. The reactivity of the catalysts still
depended strongly on the ligand structure. Catalysts with
imidazolylidene-derived ligand (Ir-A to Ir-E) were not or minor
described the use of a revolutionarily efficient [RuCl
2
(BINAP)-
(
diamine)] catalyst for the asymmetric transfer hydrogenation of
2
ketones. Encouraged by this development, considerable work
has followed on the design of new diphosphine/diamine ligands
and the evaluation of their corresponding Ru-complexes, as well
3
as elucidation of the reaction mechanism. In the case of iridium,
successful ketone hydrogenations have been achieved by
employing analogous conditions to the ruthenium systems in
combination with a number of chiral diamine and diphosphine
3
d,4
ligands.
Although asymmetric hydrogenation of ketones is
broadly utilized, the majority of these processes is base- or
additive-mediated. Limited examples of iridium catalyzed
asymmetric ketone hydrogenation under neutral conditions have
5
been developed. Despite the exclusion of base in these
reactions, other limitations occur such as the use of elevated
temperature, higher pressure of hydrogen or long reaction time.
Therefore, the development of highly reactive catalysts that can
hydrogenate ketones in the absence of additives and under mild
conditions remains desired.
reactive under 10 bar of H
2
and 80 °C. Only Ir-A (10%
conversion) and Ir-D (63% conversion) were found to be
reactive under these conditions. However, full conversions were
achieved with Ir-F to Ir-H in 1 hour. Gratifyingly, iridium catalysts
Ir-F to Ir-H could retain their high reactivity under balloon
In the last decades, a vast study has been carried out on the
pressure of H
reaction in 30 minutes. These results are noteworthy since
iridium-catalyzed hydrogenation of ketones using H typically
2
at room temperature, affording completion of the
preparation and implementation of N-heterocyclic carbenes
6
(
NHCs) in organometallic chemistry. Due to their strong binding
2
7
to metals, good stability and steric properties, NHCs offer a
1
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Chemistry - A European Journal
10.1002/chem.202002811
FULL PAPER
requires harsher conditions either in terms of higher pressure or
elevated temperature.
with 88% ee. When the methyl group on the nitrogen atom in Ir-
1 was changed to 2-propyl, the reactivity remained high, but a
dramatic loss of enantioselectivity was observed (Ir-2, 55% ee).
On the other hand, benzyl-substituted complex Ir-3 had similar
reactivity and enantioselectivity compared to Ir-1, 99%
conversion and 89% ee. A small increase in the bulkiness on the
chiral carbon, methyl to ethyl (Ir-4), enhanced the
enantioselectivity to 94% ee. No further improvement in the ee
was observed when a more sterically demanding 2-propyl
substituent was introduced on the chiral carbon (Ir-5, 84% ee) or
by replacing the benzyl group on nitrogen with a methyl group
It was encouraging that bidentate imidazolinylidene-phosphine
iridium complexes were able to catalyze the hydrogenation of
ketones under such mild and additive free conditions. We then
focused on the development of a stereoselective version of the
reaction. Thus, chiral imidazolinylidene-phosphine iridium
catalysts Ir-1 to Ir-11 were synthesized and evaluated in the
enantioselective hydrogenation of acetophenone 1 (Scheme 2).
(
Ir-6, 91% ee). Complex Ir-7, prepared from a chiral cyclic amine
Ir-cat. (1 mol%), Additive
O
OH
derivative, gave only 66% ee.
(5 mol%) or H
2
(10 bar)
Ph
i
PrOH, 80 °C
Ph
1
1a
O
OH
Ir-cat. (1 mol%), H2 (1 bar)
iPrOH, r.t., 30 min
Ph
Ph
*
1
1a
BArF
BArF
BArF
Ph
N
N
Ph
N
N
Ph
N
N
BArF
BArF
BArF
Ir
P
Ir
P
Ir
P
N
N
N
N
Bn
N
N
Ph
Ph
Ph
Ph
Ph
Ph
Ir
P
Ir
P
Ir
P
Ir-A
Ir-B
Ir-C
Ph
Ph
Ph
Ph
Ph
Ph
1
h, 82% conv.
1h, 49% conv.
5h, 87% conv.
7h, 94% conv.
9h, 99% conv.
1h, 44% conv.
5h, 96% conv.
7h, 97% conv.
9h, 98% conv.
Ir-1
Ir-2
Ir-3
t
5h, 96% conv.
5
mol% KO Bu
99% conv., 88% ee (S)
99% conv., 55% ee (S)
99% conv., 89% ee (S)
7
9
h, 96% conv.
h, 97% conv.
5
mol% HCOOH 36h, conv. n.d.
36h, conv. n.d.
36h, conv. n.d.
BArF
BArF
BArF
Bn
N
N
Bn
N
N
N
N
1h, 10% conv.
.5h, conv. n.d.
1h, conv. n.d.
0.5h, conv. n.d.
1h, conv. n.d.
No additive
a
a
0.5h, conv. n.d.a
0
Ir
P
Ir
P
Ir
P
Ph
Ph
Ph
Ph
Ph
Ph
BArF
BArF
BArF
Bn
N
N
N
N
Bn
N
N
Ir-4
Ir-5
Ir-6
9
9% conv., 94% ee (S)
99% conv., 84% ee (R)
99% conv., 91% ee (S)
Ir
P
Ir
P
Ir
P
Bn
Bn
Ph
Ph
Ph
Ph
Ph
Ph
BArF
BArF
BArF
Ir-D
Ir-E
Ir-F
Bn
N
N
Bn
N
N
Bn
N
N
1
h, 54% conv.
1h, 26% conv.
5h, 58% conv.
7h, 75% conv.
9h, 81% conv.
1h, 93% conv.
5h, 98% conv.
7h, 99% conv.
9h, 99% conv.
Ir
P
Ir
P
Ir
P
t
5h, 98% conv.
5
mol% KO Bu
Ph
Ph
Ph
7
9
h, 99% conv.
h, 99% conv.
Ph
Ph
Ph
Ir-7
Ir-8
Ir-9
5
mol% HCOOH 36h, 82% conv.
36h, conv. n.d.
36h, 72% conv.
1h, 99% conv.
9
9% conv., 66% ee (S)
80% conv., 78% ee (R)
34% conv., 69% ee (S)
1
0
h, 63% conv.
.5h, conv. n.d.
1h, conv. n.d.
0.5h, conv. n.d.
No additive
a
a
0.5h, 99% conv.a
BArF
BArF
N
N
N
N
BArF
BArF
Ph
Ph
N
N
N
N
Ir
P
Ir
P
Ph
Ph
Ir
P
Ir
P
Ph
Ph
Ph
Ph
Ph
Ph
Ir-10
Ir-11
Ir-G
h, 77% conv.
Ir-H
71% conv., 84% ee (R)
73% conv., 0% ee
1
1h, 82% conv.
5h, 98% conv.
7h, 99% conv.
9h, 99% conv.
t
5h, 95% conv.
5
mol% KO Bu
7
9
h, 97% conv.
h, 98% conv.
Scheme 2. Chiral catalyst screening under neutral conditions. Reaction
i
5
mol% HCOOH 36h, 98% conv.
36h, 90% conv.
2
conditions: 0.1 mmol 1, 1.0 mol% catalyst, H (1 bar), 2 ml PrOH, 30 min, r.t.
1
0
h, 99% conv.
.5h, 99% conv.
1h, 99% conv.
0.5h, 99% conv.
No additive
a
a
Further modification of the ligand structure by installing an
additional stereogenic center gave two pairs of diastereomeric
iridium complexes Ir-8/Ir-9 and Ir-10/Ir-11. The second
stereogenic center on the imidazolinylidene moiety in Ir-8 and Ir-
Scheme 1. Achiral catalyst screening under basic, acidic and neutral
conditions. Reaction conditions: 0.1 mmol 1, 1.0 mol% catalyst, 5 mol%
t
i
2 2
KO Bu/HCOOH or H (10 bar), 2 ml PrOH, 80 °C. a) H (balloon), 30 min, r.t.
9
had no benificial effect on the enantioselectivity and gave
lower selectivity compared to Ir-3 (78 and 69% ee respectively).
It is noteworthy that the configuration of the major formed
enantiomer switched upon inversion of the second chiral center.
Diastereomeric complexes Ir-10 and Ir-11 had comparable
reactivity but differed greatly in their enantioselectivity (Ir-10
Initially, the effect of solvent, temperature and pressure on the
enantioselectivity was studied using Ir-3 and Ir-4 before
evaluation of several chiral catalysts Ir-1 to Ir-11 (see
Supporting Information). A solvent screening showed that the
cleanest product formation accompanied with the highest
8
4% ee and Ir-11 0% ee). These results suggest that the
i
enantioselectivity was obtained in PrOH. Then, significant
enantioselectivity relies mainly on a combination of the steric
properties on both sides of the N-heterocyclic carbene.
enhancement of the ee was observed upon decreasing the
temperature, which increased from 70% ee at 80 °C to 94% ee
at temperatures <40 °C. The reaction was surprisingly
The reactivity and properties of these novel catalysts were
further studied. A kinetic study in the early stage of the
hydrogenation using Ir-2, Ir-4 and Ir-8 showed that the highest
initial turnover frequency was obtained using Ir-4, giving 19%
conversion in one minute of reaction time (Table 1). The
conversion gradually increased over the course of 20 minutes
resulting in 45% conversion in five minutes and 98% conversion
after 16 minutes. Catalyst Ir-2 showed a lower, but still high,
independent to hydrogen pressure and balloon pressure of H
was sufficient to retain high conversion and enantioselectivity
full conv., 94% ee) for Ir-4. The evaluation of catalysts Ir-1 to Ir-
1 was thus performed using 1.0 mol% of catalyst under 1 bar
2
(
1
H
i
2
pressure in PrOH, which in most cases gave complete
consumption of starting material in 30 minutes at room
temperature (Scheme 2). Complex Ir-1 gave 99% conversion
2
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Chemistry - A European Journal
10.1002/chem.202002811
FULL PAPER
reaction rate with 16% conversion after
5
minutes and
Standard conditions
completion of the reaction after 20 minutes. Catalyst Ir-8 was
found to be less reactive obtaining less than 1% of product in 2
minutes and only 3% after five minutes.
O
OH
Ir-cat. (1 mol%), H (1 bar)
2
iPrOH, r.t., 30 min
Ph
Ph
1
1a
We then attempted to pre-activate the catalyst with hydrogen
gas before addition of substrate 1. The enantioselectivity
remained unchanged, while the conversions increased
significantly. Acetophenone 1 was hydrogenated to reach 65%,
Ir-3 Full conv., 89% ee
Ir-4 Full conv., 94% ee
Deuterium labeling experiments
O
OH
Ir-4 (1 mol%), H (1 bar)
2
8
9% and 26% conversion within five minutes when using the
pre-activated catalysts of Ir-2, Ir-4 and Ir-8, compared to 16%,
5% and 3% conversion under standard conditions respectively.
Ph
CD3 iPrOH, r.t., 30 min
Ph
CD3
1a-d3 (> 95% D)
6% conv., 94% ee
1-d3 (> 95% D)
9
4
O
OH/D
H
OH/D
D
Ir-4 (1 mol%), H (1 bar)
2
+
Table 1. Conversion of acetophenone over time and the effect of pre-activated
Ph
i
Ph
1b, 45%
Ph
d - PrOD, r.t., 30 min
8
1
1c, 55%
8% conv., 94% ee
catalyst.
9
O
OH
O
OH/D
H
OH/D
D
Ir-cat. (1 mol%), H2 (1 bar)
PrOH, r.t.
Ph
Ir-4 (1 mol%), D (1 bar)
2
i
*
+
Ph
iPrOH, r.t., 30 min
Ph
Ph
Ph
Ph
1c, 48%
8% conv., 94% ee
1
1a
1
1b, 52%
9
O
OH/D
H
OH/D
D
Ph
1c, 0%
Ir-4 (1 mol%), H (1 bar)
2
+
i
Ph
d - PrOD, r.t., 30 min
1
1
1b, 100%
Full conv., 94% ee
Excluding direct hydrogenation
Activated
Ir-3 (1 mol%), N2
O
OH
iPrOH, r.t., 30 min
Ph
Ph
1
1a
5
7% conv., 89% ee
Excluding transfer hydrogenation
O
OH
Ir-3 (1 mol%), H (20 bar)
2
+
Ph
DCM, r.t., 2 h
Ph
1a, 80%
Ph
O
20%
Ph
1
Full conv., 85% ee
Scheme 3. Mechanistic studies.
Catalyst
Reaction condition
Time
conv.
ee
a
Ir-2
Ir-2
Ir-4
Ir-4
Ir-8
Ir-8
pre-activated
5 min.
5 min.
5 min.
5 min.
5 min.
5 min.
65%
16%
89%
45%
26%
3%
55% (S)
55% (S)
94% (S)
94% (S)
78% (R)
-
Thereafter, the mechanism of the hydrogenation was studied
Scheme 3). 1-d was prepared and subjected to standard
(
3
standard condition
conditions without the loss of any deuterium in a-position,
a
pre-activated
indicating that the reaction does not involve the hydrogenation of
i
an enol. By using d
8
-PrOD as the solvent and employing
standard condition
hydrogen gas, a mixture of products was obtained with a
deuterium incorporation of 55% on the carbinol carbon 1c. A
similar amount of 48% 1c was obtained when deuterium gas in
a
pre-activated
i
PrOH was used. To verify that the formation of a mixture of
standard condition
1
b/1c did not arise from a hydride exchange between any of the
i
Ir-hydride intermediates and the solvent, d
a solvent hydrogenating acetophenone 1 to 1b in a clean
manner. Since our developed ligand structures lack a
1
-PrOD was used as
i
Reaction conditions: 0.1 mmol 1, 1.0 mol% catalyst, H
2
(1 bar), 2 ml PrOH, 30
atmosphere (balloon)
i
min, r.t. a) Catalyst in 1 ml PrOH was stirred under H
2
i
for 15 min before 1 in 1 ml PrOH was added.
heteroatom that can act as a proton acceptor, a transfer
hydrogenation pathway where in a single step the proton and
the hydride are abstracted from the solvent is unlikely. However,
stepwise pathways involving external delivery of the proton (i.e.
from the solvent), after migratory insertion of a hydride from the
Ir-species, are reported for the hydrogenation of ketones using
In order to shed further light on the nature of the active
catalyst, a reaction using 10 mol% of Ir-4 was analyzed after
completion and showed that over 80% of the theoretical amount
of cyclooctane was generated under balloon pressure of H
2
in 30
minutes. Moreover, 1 equiv. of Ir-4 and 2 equiv. of 1 together
12
i
Ir-NHC complexes. To test this option, where hydrogen gas is
with 5 equiv. of PrOH were reacted in d
8
-THF (balloon pressure
i
not involved, activated Ir-3 reacted with 1 in PrOH under N
2
of H , 1 h) and >95% of the theoretical amount of cyclooctane
2
1
atmosphere giving 57% conversion in 30 minutes without any
loss of selectivity (89% ee). Additionally, from the solvent
screening, 41% and full conversion was observed when the
reaction was performed in toluene and DCM, respectively (Ir-3,
was observed by H-NMR analysis. To this reaction mixture was
then added 100 equiv. of 1, which was hydrogenated in 79% in
3
0 minutes. These combined results clearly indicate that during
the pre-activating period, the COD ligand is hydrogenated into
cyclooctane, and this results in the formation of the active
hydrogenation catalyst.
2
2
0 bar of H , see Supporting Information) and therefore a direct
hydrogenation mechanism cannot be excluded. Based on these
results, we propose two coexisting active hydrogenation
mechanisms which pathways are given in Scheme 4. Starting
from Ir-4, the pre-catalyst gets activated under hydrogen
3
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Chemistry - A European Journal
10.1002/chem.202002811
FULL PAPER
atmosphere forming hydrogenation active dihydride species A.
After coordination of the substrate (intermediate B), migratory
insertion of a hydride to the carbonyl carbon takes place to form
C at which point the pathway can diverge. Following a hydride
transfer pathway, the proton is delivered externally by the
solvent and regeneration of the catalyst occurs by hydride
abstraction of the formed Ir-isopropoxide species D.
Alternatively, the Ir-alkoxide bond in C can be cleaved by the
ligated dihydrogen forming E and subsequent coordination of a
new molecular hydrogen regenerates A. The reversibility of
these hydrogenation/dehydrogenation steps via D can possibly
BArF
O
OH
Bn
N
N
Ir-4 (1 mol%), H
2
(1 bar)
Ar
2
R
i
PrOH, r.t., 30 min
Ar
R
Ir
P
Ph
-13
2a-13a
Ph
Ir-4
OH
OH
OH
OH
Br
Cl
F
2
a
3a
4a
5a
9
9% conv.
4% ee
99% conv.
94% ee
99% conv.
99% conv.
94% ee
9
94% ee
account for the H/D scrambling in the product when D
2
gas or
i
OH
OH
OH
OH
d
8
-PrOD is used. Interestingly, the selectivity in DCM (85% ee)
i
is close to the selectivity observed in PrOH (89% ee), what
suggests a similar coordination of the substrate upon iridium
regardless of the underwent pathway. The slightly lower value in
DCM can be explained by the observed, reversible, ether
formation.
3
F C
6a
7a
8a
9a
Cl
CF
3
9
9% conv.
5% ee
99% conv.
95% ee
99% conv.
96% ee
99% conv.
90% ee
9
OH
OH
OH
OH
Et
BArF
NHC
Bn
N
N
1
0a
11a
12a
13a
NO
9% conv.
4% ee
2
=
P
Ir
Ir
P
9
99% conv.
92% ee
99% conv.
90% ee
99% conv.
93% ee
Ph
Ph
9
Ir-4
>
95% COD
H
2
elimination detected
Scheme 5. Substrate scope. Reaction conditions: 0.1 mmol 1, 1.0 mol%
i
2
catalyst, H (1 bar), 2 ml PrOH, 30 min, r.t.
NHC
H2
Ir
O
P
H
Conclusion
H A
1
H
2
To summarize, the development of a new library of NHC-
phosphine iridium complexes was reported and their efficiency in
the hydrogenation of ketones was demonstrated. On the basis of
an initial screening of achiral ligand backbones, an asymmetric
version of the reaction was designed and optimized, obtaining
up to 96% ee for acetophenone derivatives. The extent of chiral
induction greatly depended on the substitution pattern on both
sides of the imidazolinylidene moiety. Remarkably, these
catalysts showed very high reactivity under balloon pressure of
Hydride
transfer
Direct
hydrogenation
NHC
H2
Ir
NHC
NHC
H
Ir
H O
2
P
O
P
Ir
P
H
Ph
H D
H B
H E
i
hydrogen in PrOH, with most reactions being complete in 30
Product
Product
minutes. Upon pre-activation of the most enantioselective
catalyst, 89% conversion could be obtained in only 5 minutes
reaction time. Notably, these novel bidentate NHC-phosphine
catalysts performed well under additive-free conditions, whereas
a base is often required in the hydrogenation of ketones. During
the activation period, COD is reduced and eliminated as
cyclooctane. Relying on mechanistic experiments, a hydride
transfer pathway as well as a direct hydrogenation pathway are
proposed.
NHC
H2
Ir
OH
P
O
H C Ph
Scheme 4. Proposed catalytic pathways.
Finally, the substrate scope was investigated and the catalyst
maintained high reactivity in most cases with the reaction being
complete in 30 minutes (Scheme 5). The hydrogenation was
successful for a wide range of substituted acetophenones. The
nature of the para-substituent showed not to interfere with the
selectivity. Thus, both electron-donating methyl, as well as
various weakly to strong electron-withdrawing groups were well
tolerated giving 94-96% ee’s (2-6). A similar trend was observed
for meta-substitutions giving access to 90-96% ee’s with full
conversion (7-10). Furthermore, ortho-methyl substituted
acetophone 11 resulted in 92% ee and naphthyl ketone 12 was
hydrogenated in 90% ee. Prolonging the ketone side-chain to
ethyl (13) gave equal selectivity compared to 1 (93% ee).
Unfortunatally, acetylated heteroarmatic substrates were found
Experimental Section
The synthetic procedures and characterization data of all new iridium
complexes as well as their intermediates is given in the Supporting
Information.
Representative procedure for the hydrogenation of aryl ketones. An
oven-dried glass vial equipped with magnetic stirring bar was charged
i
with substrate (0.1 mmol), iridium complex (1.0 mol%) and dry PrOH (2.0
ml). The vial was placed in a low-pressure hydrogenation apparatus,
purged three times with nitrogen, purged three times with hydrogen gas
and then pressurized to 1.0 bar with hydrogen gas. After stirring for 30
minutes at room temperature, the pressure was released and the solvent
was removed under vacuum. The crude product was then purified by
1
3
to inhibit the reaction.
2
column chromatography on silica gel (pentane/Et O, 1/1) to give the
4
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1
corresponding product. Conversions were determined by
H
NMR
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Acknowledgements
[
The Swedish Research Council (VR), Stiftelsen Olle Engkvist
Byggmästare, The Swedish Energy Agency, SYNFLOW (FP7)
and the Knut and Alice Wallenberg foundation (KAW 2016:0072
[
[
12] M. V. Jiménez, J. Fernández-Tornos, F. J. Modrego, J. J. Pérez-
Torrente, L. A. Oro, Chem. Eur. J. 2015, 21, 17877-17889.
&
2018:0066) supported this work. J.J. thanks the Chulabhorn
13] Evaluated heteroaromatic substrates include 2-acetylpyridine, 3-
acetylpyridine, 4-acetylpyridine, 2-acetylfuran and 2-acetylthiophene.
Graduate Institute, Chulabhorn Royal Academy, Thailand for an
exchange scholarship to Stockholm University. The authors
thank Dr. T. Singh, Dr. B. Peters and Dr. J. Zheng for useful
discussions, Dr. X. Sheng for help with the kinetic study and Dr.
C. Margarita for proofreading the manuscript.
Keywords: ligand development • asymmetric hydrogenation • N-
heterocyclic carbene • iridium catalysis • ketones
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TOC Image
Cat.
R2
R3
Ph
BArF
OH
O
H2
R1
N
N
Ar
R
Ar
R
Ir
P
Catalyst development
Reactivity study
Ph
Additive free methodology
Balloon pressure H2,
r.t., 30 min.
Up to 96% ee
6
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