Highly enantioselective amido iridium catalysts for the hydrogenation of simple ketones

Article abstract of DOI:10.1002/anie.201004665

New family of cats: Tailormade amido iridium catalysts with simple structures and no P ligands show excellent enantioselectivities and activities in the asymmetric hydrogenation of simple ketones (see scheme; Cyellow, Ngreen, Oblue, Irred). These catalysts may thus be the key to ecologically and economically optimized value creation

Full text of DOI:10.1002/anie.201004665

DOI: 10.1002/anie.201004665
Asymmetric Catalysis
Highly Enantioselective Amido Iridium Catalysts for the
Hydrogenation of Simple Ketones**
Torsten Irrgang, Denise Friedrich, and Rhett Kempe*
In the production of chiral compounds chemocatalysis com-
petes with other techniques such as, for example, the
resolution of racemates, the “chiral pool” approach, and
biocatalysis. Highly enantioselective chemocatalysts based on
simple and inexpensive ligands could drastically increase the
importance of chemocatalysis.[1] We report here on highly
enantioselective phosphorus-free catalysts with a novel struc-
ture for the hydrogenation of simple ketones.[2] The chiral
ligands can be synthesized in a one-pot reaction starting from
inexpensive chemicals. The modular nature of this synthesis
ensures the introduction of a broad variety of substitution
patterns. The catalyst synthesis starts with air- and moisture-
stable substrates. Until now, chemocatalysts based on the
phosphane–ruthenium–diamine complexes developed by
Noyori, catalysts related to this structural type,[3,4] and more
complex chelate systems[5] have been the most successful
catalysts for the asymmetric hydrogenation of ketones. In
contrast, phosphorus-free (iridium) catalyst systems are
drastically less efficient and/or enantioselective in this asym-
metric hydrogenation.[6]
Scheme 1. Synthesis of 2 and 3 (a: R1 =tBu, R2 =H, R3 =R4 =CH3; b:
R1 =C6H5, R2 =CH2CH(CH3)2, R3 =R4 =CH3; c: R1 =tBu, R2 =CH2CH-
(CH3)2, R3 =R4 =CH3; d: R1 =C6H5, R2 =CH(CH3)2, R3 =R4 =CH3; e:
R1 =C6H5, R2 =CH2CH3, R3 =R4 =CH3; f: R1 =C6H5, R2 =CH3,
R3 =R4 =CH3).
Imidazo[1,5-b]pyridazine-substituted amines, which can
serve as amido ligands to stabilize early- and late-transition-
metal complexes, can be synthesized by ring transformation
and a subsequent cyclocondensation reaction.[7] Starting from
2-amino-5-methyl-1,3,4-oxadiazolium halides 1[8] (Scheme 1)
amino alcohol substituted imidazo[1,5-b]pyridazines 2 were
prepared in a one-pot reaction in yields ranging from 50 to
60%. The iridium amido complexes 3 were prepared in
quantitative yields from 2 and [{IrOCH3(cod)}2][9] (cod = 1,5-
cyclooctadiene) by methanol elimination in THF at room
temperature (Scheme 1). The molecular structure of 3b is
shown in Figure 1.
The iridium atom is stabilized by the formation of a five-
membered chelate (N1, N2, C9, N4, Ir). The Ir–Namido bond
[2.031(3) ꢀ] is significantly shorter than the Ir–Npyridazine bond
[2.149(4) ꢀ)] indicating the localization of the negative
Figure 1. Molecular structure of 3b (ORTEP plot); non-carbon atoms
at the 50% probability level, H atoms not shown. Selected bond
lengths [ꢀ] and angles [8]: Ir1–N1 2.149(4), Ir1–N4 2.031(3), N1–N2
1.383(5), N2–C9 1.343(5), N4–C9 1.345(5); N1-Ir1-N4 80.6(13), C9-
N4-Ir1 113.1(3), N2-N1-Ir1 106.2(2), N2-C9-N4 118.3(4), N3-C9-N4
132.3(4).
[*] Dr. T. Irrgang, Dr. D. Friedrich, Prof. Dr. R. Kempe
Chair of Inorganic Chemistry II, University of Bayreuth
95440 Bayreuth (Germany)
Fax: (+49)921-55-2157
E-mail: kempe@uni-bayreuth.de
charge of the ligand at the Namido atom. The hydroxyalkyl
moiety forms a hydrogen bond with N3 of the imidazole ring
[d(O1H10···N3) = 1.949 ꢀ].
Dr. T. Irrgang
AIKAA-Chemicals GmbH
Iridium amides can undergo heterolytic H2 cleavage to
generate amino iridium hydrides,[10] which are analogues of
amino ruthenium hydrides, the proposed intermediates in the
hydrogenation of ketones with state-of-the-art phosphane–
ruthenium–diamine ketone catalysts.[3,4,11] Additional evi-
dence for this analogy is provided by recently developed
rhodium amide catalysts.[12] Hydrogenation experiments
Kꢁmmereigasse 11, 95444 Bayreuth (Germany)
[**] This work was supported by NanoCat, an International Graduate
Program within the Elitenetzwerk Bayern. We also thank the Otto-
Warburg-Chemie-Stiftung for financial support and Dr. G. Glatz for
his support with the X-ray crystal-structure analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004665.
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2183

Communications
Table 1: Asymmetric hydrogenation of propiophenone.
Entry
Precatalyst
Acetone/
propiophenone
Conv.
[%][b]
ee [%][b]
1
2
3
4
5
6
7
8
3a[a]
3a[a]
3b[a]
3b[a]
3c[a]
3c[a]
3d[a]
3d[a]
3e[a]
3e[a]
3 f[a]
3 f[a]
4b[c]
4b[d]
4b[d]
–
2:1
–
2:1
–
2:1
–
2:1
–
2:1
–
2:1
–
–
2:1
>99
>99
>99
>99
>99
>99
>99
>99
>99
78
0
0
71
>99
37
>99
65
97
39
89
31
9
10
11
12
13
14
15
>99
51
0
93
78
0
71
99
90
[a] Reaction conditions see Figure 2, 0.05 mol% 3a–f. [b] Conversion
and ee were determined by GC. [c] 0.05 mol% 4b, 24 h, 20 bar H2, RT.
[d] 0.05 mol% 4b, KOtBu/4b 250:1, 24 h, 20 bar H2, RT.
Figure 2. Hydrogenation of propiophenone with 3b in the presence of
KOtBu.
to fine-tune the solubility of the catalyst. An acetone/
propiophenone ratio of 2:1 is optimal to reach high enantio-
selectivity and to maintain a high level of activity in the
conversion of the prochiral ketone.
The reaction of 3 with KOtBu is accompanied by a clear
color change from dark turquoise to red and gives rise to the
bimetallic complex 4. The molecular structure of 4b is shown
in Figure 3; that of 4a is given in the Supporting Information.
under the conditions listed in Figure 2 revealed low activity
and enantioselectivity for all investigated complexes 3a–f.
The addition of KOtBu leads to quantitative conversion with
3b as a precatalyst with catalyst loadings of 1, 0.5, 0.1, and
0.05 mol% (Figure 2). KOtBu itself is a catalyst for the
hydrogenation of ketones under drastic conditions,[13] and its
potassium cations accelerate the reaction rate of phosphane–
ruthenium–diamine complexes.[14a]
With a decrease of the catalyst loading the enantioselec-
tivity increases significantly. Without KOtBu and with
1 mol% of 3b a conversion of only 33% and an enantiose-
lectivity of only 3% ee is observed. Two conclusions can be
drawn from these observations. Firstly, KOtBu is needed as an
additive. Secondly, the enantioselectivity of the catalyst
system seems to increase during the hydrogenation. Two
phenomena could explain the increase of the enantioselec-
tivity with progressing catalysis: autocatalysis as well as the
formation of a yet more enantioselective species during the
hydrogenation. The addition of (S)-(À)- or (R)-(+)-1-phenyl-
propan-1-ol (autocatalysis) did not significantly increase the
enantioselectivity. If a more enantioselective catalyst species
is formed during catalysis, the addition of a (non-prochiral)
ketone, which is hydrogenated in parallel, could increase the
enantioselectivity. The increase in enantioselectivity could
result from the fact that the more enantioselective catalyst
species is already formed before a significant amount of the
unwanted enantiomer is produced. Acetone turned out to be
a useful additive. The catalytic performance (hydrogenation
of propiophenone) of 3a–f with KOtBu and acetone was
examined (Table 1). The addition of acetone as a cosubstrate
leads to an increase in enantioselectivity for all chiral catalyst
systems (entries 3–12). The enantioselectivity of the catalyst
can be optimized by adjusting the steric bulk of the
substituent at the asymmetric carbon atom of the amino
alcohol such that selectivities of > 99% ee can be obtained
(entries 4 and 6) under the given conditions. The substituent
at the imidazole ring is little effect on the ee and might be used
Figure 3. Molecular structure of 4b. (ORTEP plot); non-carbon atoms
at the 50% probability level, H atoms not shown. Selected bond
lengths [ꢀ] and angles [8]: N1–K2 2.748(10), N4–Ir1 2.007(10), N4–K2
3.313(9), O1–Ir1 1.992(9), N1-K2-N4 45.4(3).
The hydroxy moiety is deprotonated by KOtBu, and an
iridium amido–alkoxo complex is formed. The chiral carbon
atoms of the amino alcohol moiety of 2b–f are in close
proximity to the iridium atom through the formation of five-
membered C-O-Ir-N-C chelates which may explain the
increased enantioselectivity of the heterobimetallic com-
plexes. The potassium atom in 4b has strained h2-N,N
coordination. The binding of the potassium atom to the
amido N atom may enhance the heterolytic H2 cleavage.[11b,14]
2184
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Angew. Chem. Int. Ed. 2011, 50, 2183 –2186

If 4b is used as a catalyst without added base, the reaction
mixture turns blue, which indicates formation of 3b and
hydrogenation becomes very slow (Table 1, entry 13). The
products of the catalysis compete with the OH moiety of the
ligand in terms of metalation. To shift the equilibrium towards
4b, an excess of KOtBu is essential under catalysis conditions
(Table 1, entry 14 and 15).
inexpensive catalyst structures for enantioselective syntheses
and thus a higher acceptance of chemocatalysts in life-science
applications.
Received: July 28, 2010
Revised: October 18, 2010
Published online: January 26, 2011
Having optimized important reaction parameters like the
ligand, co-catalyst, and ketone additive, we set out to broaden
the substrate scope. The aryl ketones shown in Figure 4 were
hydrogenated with excellent enantioselectivities (> 99% ee)
using the catalyst system based on 3b.
Keywords: alcohols · amido ligands · asymmetric catalysis ·
hydrogenation · iridium
.
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0.05 mol% catalyst on a reaction scale of 100 mL with
quantitative conversion and > 99% ee.
In conclusion, we have introduced a modular phosphorus-
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complexes, which hydrogenate simple ketones with excellent
enantioselectivities. We showed that highly enantioselective,
but structurally simpl catalysts can be obtained easily from
inexpensive starting materials. The new lead structure pre-
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