Enantioselective hydrogenation of α-substituted acrylic acids catalyzed by iridium complexes with chiral spiro aminophosphine ligands

Article abstract of DOI:10.1002/anie.201204363

Highly active: Iridium complexes with chiral spiro aminophosphine ligands were synthesized and applied as catalysts for the asymmetric hydrogenation of α-substituted acrylic acids (see scheme). The complexes were highly active catalysts, showing turnover frequencies of up to 6000 h^-1, and catalyst loadings could be reduced to 0.01 mol %. Copyright

Full text of DOI:10.1002/anie.201204363

Angewandte
Chemie
DOI: 10.1002/anie.201204363
Homogeneous Catalysis
Enantioselective Hydrogenation of a-Substituted Acrylic Acids
Catalyzed by Iridium Complexes with Chiral Spiro Aminophosphine
Ligands**
Shou-Fei Zhu, Yan-Bo Yu, Shen Li, Li-Xin Wang, and Qi-Lin Zhou*
The transition-metal-catalyzed asymmetric hydrogenation
reactions attract long-lasting interest from both academic
research and industrial production.[1] The development of
chiral ligands is the essential impetus for the asymmetric
hydrogenation reactions. During the past decades, chiral P,N
ligands having both phosphorus and nitrogen atoms as the
coordinating groups become popular in the hydrogenation
reactions.[2] Generally, molecules with sp2 nitrogen atoms,
such as oxazoline and pyridine, are required for achieving
good results for the chiral P,N ligands. Although several
phosphine amine ligands containing primary amine moieties
have been successfully applied in the highly enantioselective
hydrogenation of ketones,[3] to our knowledge, such ligands
have not been applied successfully in the asymmetric hydro-
genation of olefins. Herein we report the preparation of novel
Scheme 1. Synthesis of chiral spiro aminophosphine ligands and
chiral spiro aminophosphine ligands bearing a primary amine
moiety 3 (Scheme 1) and their applications in the hydro-
genation of a,b-unsaturated carboxylic acids. The iridium
complexes 5 derived from the chiral spiro aminophosphine
ligands showed unprecedentedly high activity (turnover
numbers (TONs) up to 10000; turnover frequencies (TOFs)
up to 6000 hÀ1) and enantioselectivity (94–99% ee). The
primary amine moiety in the catalysts 5 is the key for
obtaining high activity and enantioselectivity.
corresponding iridium complexes. Reaction conditions: a) Zn(CN)2,
[Pd(PPh3)4], DMF, 84–88%; b) LiAlH4, THF, reflux, 90–94%;
c) 1) ClCOOEt, pyridine, THF; 2) LiAlH4, THF, reflux; 60%;
d) [{Ir(cod)Cl}2], NaBArF, CH2Cl2, reflux, 76–91%. BArF =tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate, cod=cyclooctadiene, Tf=trifluoro-
À
methanesulfonyl. The hydrogen atoms, cod ligand, and anion (BArF
were omitted for clarity. Thermal ellipsoids are set at 60% probability.
Selected bond lengths [ꢀ] and angles [8]: Ir–N 2.152(4), Ir–P
2.3394(12); N-Ir-P 89.63(13).
)
Chiral spiro aminophosphine ligands 3 and 4 were easily
prepared starting from optically pure 1 (Scheme 1).[4] Palla-
dium-catalyzed cyanation of 1 (step a) followed by LiAlH4
reduction (step b) afforded ligands 3 in good yield. Ligands 4,
which have an N-methyl group, were prepared from 3 through
condensation with ethyl chloroformate and LiAlH4 reduction
in one pot (step c). The iridium complexes 5 were prepared by
refluxing a mixture of [{Ir(cod)Cl}2], 3 or 4, and NaBArF in
dichloromethane for two hours (step d). Complexes 5 were
stable enough to be purified by silica gel column chromatog-
raphy and stored in air without degradation for a few months.
The structure of complex (Sa)-5a was proved by an X-ray
diffraction analysis of a single crystal.[5] According to the
crystal structure, (Sa)-3a acts as a chelating P,N ligand and
creates a rigid chiral pocket around the iridium center.
The asymmetric hydrogenation of a-substituted acrylic
acids 6 (for structures see Table 2) is of highly practical value
because the products, optically pure a-substituted propionic
acids, include important biologically active compounds. For
example, ibuprofen (7a) and naproxen (7 f),[6] two well-
known non-steroid anti-inflammatory drugs, can be readily
prepared by asymmetric hydrogenation of the corresponding
a-aryl acrylic acids. Although chiral ruthenium catalysts
usually give high enantioselectivity in the asymmetric hydro-
genation of a-substituted acrylic acids, most of these catalysts
require high hydrogen pressure (e.g., 100 atm) to achieve
complete conversion and high enantioselectivity.[7] The high
pressure markedly limits the practical application of the
reaction. Rhodium/diphosphine[8] and iridium/phosphine oxa-
zoline[9] catalysts have also been used for the asymmetric
hydrogenation of a-aryl acrylic acids; however, these catalysts
show unsatisfactory activity, enantioselectivity, or both.
Furthermore, the asymmetric hydrogenation of a-alkyl-sub-
stituted acrylic acids[10] is highly underdeveloped compared to
that of a-aryl-substituted acrylic acids. As part of our
[*] Prof. S.-F. Zhu, Y.-B. Yu, S. Li, L.-X. Wang, Prof. Q.-L. Zhou
State Key Laboratory and Institute of Elemento-organic Chemistry
Nankai University, Tianjin 300071 (China)
E-mail: qlzhou@nankai.edu.cn
Homepage: http://zhou.nankai.edu.cn/
[**] We thank the National Natural Science Foundation of China and the
National Basic Research Program of China (2011CB808600,
2012CB821600), and the “111” project (B06005) of the Ministry of
Education of China for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204363.
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continuing efforts to develop asymmetric hydrogenation of
unsaturated carboxylic acids,[11] we tried iridium-catalyzed
asymmetric hydrogenation of a-substituted acrylic acids with
new chiral spiro aminophosphine ligands 3 or 4.
(Table 1, entry 6). This result represents the highest level of
activity and enantioselectivity of catalysts in the asymmetric
hydrogenation of a-substituted acrylic acids. In contrast, (Sa)-
8, an iridium complex of the ligand SpiroAP[3b] bearing an
aromatic amino group, did not catalyze the hydrogenation of
6a (Table 1, entry 7). The iridium complex (Sa,S)-9 derived
from chiral spiro phosphine oxazoline ligands,[12] which
exhibit excellent activity and enantioselectivity in the hydro-
genation of trisubstituted a,b-unsaturated carboxylic
acids,[11c,d] was also less efficient in the present hydrogenation
reaction (Table 1, entry 8). Besides Cs2CO3, other bases such
as Na2CO3 and Et3N were also suitable additives for achieving
good results (Table 1, entries 9 and 10); however, the reaction
rate decreased dramatically in the absence of base (entry 11).
We speculated that the base promoted the formation of the
carboxy anion of the substrate, which then chelates to the
iridium center of the catalyst more easily than the acid itself,
and thus accelerated the hydrogenation reaction.
Under the optimal reaction conditions, the hydrogena-
tions of various a-substituted acrylic acids were conducted
with 0.1 mol% of catalyst (Sa)-5c at 6 atm or ambient
hydrogen pressure (Table 2). All the tested acids, regardless
of the substituents on the phenyl rings, were rapidly hydro-
genated with extremely high enantioselectivity (96–99% ee;
Table 2, entries 1–6). Several chiral non-steroid anti-inflam-
matory drugs, including ibuprofen (7a), flurbiprofen (7e),
and naproxen (7 f), were prepared with excellent yields and
enantioselectivities (Table 2, entries 1, 5, and 6). a-Alkyl
acrylic acids were also suitable substrates for this reaction,
affording the corresponding saturated acids with high to
excellent enantioselectivities (Table 2, entries 7–12). Note
that this hydrogenation tolerated a broad range of functional
groups. For example, acrylic acids bearing an ester (6j), an
ether (6c, 6 f, 6k, 6l), or a halogen substituent (6d, 6e) could
be hydrogenated smoothly with 100% conversion and high
enantioselectivities. These new catalysts show an advance
over known chiral catalysts for the asymmetric hydrogenation
of a-substituted acrylic acids owing to high activity, excellent
enantioselectivity, and wide substrate scope.
To our delight, the chiral spiro aminophosphine ligands
exhibited excellent activity and enantioselectivity for the
asymmetric hydrogenation of 6a. In the presence of
0.1 mol% (ratio substrate/catalyst (S/C) = 1000) of catalyst
(Sa)-5c, the hydrogenation of 6a was completed within ten
minutes (with a TOF of 6000 hÀ1) to afford the desired
product 7a with excellent enantioselectivity (98% ee; Table 1,
entry 3). Iridium catalysts 5 with less bulky P-aryl groups
showed slightly lower activity and enantioselectivity (Table 1,
entries 1 and 2). Although the catalyst (Sa)-5d, which has an
N-methyl group, also showed excellent enantioselectivity, the
hydrogenation reaction was not completed after 18 h
(Table 1, entry 4). Catalyst (Sa)-5c exhibited remarkably
high catalytic activity in the asymmetric hydrogenation of
6a. In the presence of 0.1 mol% of catalyst (Sa)-5c, the
hydrogenation reaction proceeded at ambient hydrogen
pressure (Table 1, entry 5). When the catalyst loading was
further reduced to 0.01 mol% (S/C = 10000), the reaction was
completed within eight hours at 6 atm hydrogen pressure
without significant diminishment of the enantioselectivity
Table 1: Asymmetric hydrogenation of a-(4-isobutylphenyl)acrylic acid
6a.[a]
Entry
Catalyst
Base
Time
Conv [%][b]
ee [%][c]
1
2
3
4
(Sa)-5a
(Ra)-5b
(Sa)-5c
(Sa)-5d
(Sa)-5c
(Sa)-5c
(Sa)-8
(Sa,S)-9
(Sa)-5c
(Sa)-5c
(Sa)-5c
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
Et3N
2 h
1 h
10 min
18 h
4 h
100
100
100
44
100
100
0
94 (R)
96 (S)
98 (R)
98 (R)
99 (R)
97 (R)
–
45 (R)
98 (R)
98 (R)
91 (R)
5[d]
6[e]
7
8 h
24 h
24 h
30 min
15 min
24 h
8[f]
9
36
In addition to a-substituted acrylic acids, other typical
unsaturated carboxylic acids, such as a-methyl cinnamic acid
(10a), a-phenyl cinnamic acid (10b), tiglic acid (10c), a-
phenyl butanoic acid (10d), and a-benzyloxy cinnamic acid
(10e) can also be hydrogenated by using catalyst (Sa)-5c
(Scheme 2), providing the corresponding chiral carboxylic
acids in high yield (93–98%) and excellent enantioselectivity
(95–99.3% ee). These examples demonstrate that the present
chiral spiro iridium catalysts derived from aminophosphine
ligands 3 have broad applications in the synthesis of chiral
carboxylic acids.
100
100
38
10
11
none
[a] Reaction conditions: 0.5 mmol scale, [substrate]=0.25 molLÀ1 in
MeOH, S/C=1000, 0.5 equiv Cs2CO3 as additive, PH =6 atm, 458C.
2
[b] Determined by 1H NMR spectroscopy. [c] Determined by chiral GC
analysis of the corresponding methyl ester with a Varian CP7502 column
(see the Supporting Information for details), absolute configuration was
determined by the sign of optical rotation. [d] The reaction was
performed under ambient hydrogen pressure. [e] Reaction conditions:
1 mmol scale, [substrate]=0.25 molLÀ1 in MeOH, S/C=10000, 5 equiv
It has been reported that the terminal double bond of
olefins can isomerize to the more stable internal double bond
in iridium-catalyzed hydrogenation reactions.[13] To determine
the mode of addition of hydrogen to the double bond of the
substrate in the (Sa)-5c-catalyzed hydrogenation of a-alkyl-
substituted acrylic acids, we conducted deuterium labeling
studies (Scheme 3). 1H NMR spectroscopy analysis of the
products of the reactions of 6g and 6j with D2 catalyzed by
(Sa)-5c under standard reaction conditions showed that the
NEt3 as additive, PH =6 atm, 608C. [f] S/C=200.
2
2
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Chemie
Table 2: Asymmetric hydrogenation of a-substituted acrylic acids.[a]
Entry Substrate
Product PH
Time
Yield ee
[%] [%]
2
6 atm
ambient 4 h
10 min 98
98
98
99
1
7a
7b
7c
7d
6a
6 atm
ambient 4 h
15 min 97
95
98
98
2
6b
Scheme 2. Hydrogenations of a,b-unsaturated carboxylic acids. Reac-
tion conditions: 0.5 mmol scale, [substrate]=0.25 molLÀ1 in MeOH,
6 atm
ambient 4 h
15 min 98
96
98
99
S/C=400, 0.5 equiv Cs2CO3 as additive, PH =6 atm, 458C.
2
3
6c
6 atm
ambient 8 h
30 min 98
96
97
98
4
6d
6 atm
ambient 4 h
15 min 99
98
96
97
5
7e
7 f
6e
Scheme 3. Deuterium labeling studies.
6 atm
ambient 4 h
15 min 99
98
97
98
6
6 f
aminophosphine ligands made these catalysts highly efficient
for the hydrogenation of a,b-unsaturated carboxylic acids.
6 atm
ambient 4 h
15 min 99
98
98
98
7
7g
7h
7i
6g
6 atm
25 min 97
95
96
96
8
Experimental Section
General hydrogenation procedure:
ambient[b] 4 h
6h
A hydrogenation tube was
charged with a stir bar, a-substituted acrylic acids 6 (0.5 mmol),
catalyst (Sa)-5c (0.9 mg, 0.0005 mmol), Cs2CO3 (82 mg, 0.25 mmol) in
an argon-filled glovebox. Methanol (2 mL) was injected into the
hydrogenation tube by a syringe while stirring. The hydrogenation
tube was then put into an autoclave. The autoclave was purged three
times with hydrogen. The autoclave was then charged with hydrogen
to 6 atm, and the reaction mixture was stirred at 458C for a specified
time before releasing the hydrogen. The reaction mixture was
acidified with 3n HCl and extracted with Et2O. Evaporation of the
solvent afforded the crude product. The conversion of the substrate
was determined by 1H NMR spectroscopy. The product was con-
verted into the corresponding ester or amide and the ee value was
determined by GC, HPLC, or supercritical fluid chromatography
(SFC) with a chiral column. The hydrogenation reaction at ambient
pressure was performed in a Schlenk tube connected with a hydrogen-
filled balloon.
6 atm
30 min 97
96
94
98
9
ambient[b] 4 h
6i
6 atm
ambient 4 h
15 min 99
96
95
97
10
7j
6j
6 atm
ambient 4 h
15 min 94
98
96
96
11
7k
7l
6k
6 atm
ambient 4 h
15 min 98
97
95
98
12
6l
[a] Reaction conditions are the same as those of Table 1, entry 3 (for
PH =6 atm) and entry 5 (for PH =ambient pressure). See the Supporting
Information for detailed analyses of hydrogenation products;
2
2
[b] S/C=500.
Received: June 5, 2012
Published online: && &&, &&&&
deuterium atoms were added only to the original double bond
of the substrates, which indicated that no double bond
isomerization occurred during the reaction.
In summary, we developed new chiral spiro aminophos-
phine ligands and proved their iridium complexes are highly
efficient catalysts for the asymmetric hydrogenation of a-
substituted acrylic acids. Different chiral a-substituted car-
boxylic acids have been synthesized under very mild reaction
conditions at low catalyst loadings with high enantioselectiv-
ities. The chelating primary amine moiety of the chiral spiro
Keywords: asymmetric hydrogenation · carboxylic acids ·
.
homogeneous catalysis · iridium · N,P-ligands
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Communications
Homogeneous Catalysis
S.-F. Zhu, Y.-B. Yu, S. Li, L.-X. Wang,
Q.-L. Zhou*
&&&& — &&&&
Enantioselective Hydrogenation of a-
Substituted Acrylic Acids Catalyzed by
Iridium Complexes with Chiral Spiro
Aminophosphine Ligands
Highly active: Iridium complexes with
chiral spiro aminophosphine ligands
were synthesized and applied as catalysts
for the asymmetric hydrogenation of a-
substituted acrylic acids (see scheme).
The complexes were highly active cata-
lysts, showing turnover frequencies of up
to 6000 hÀ1, and catalyst loadings could
be reduced to 0.01 mol%.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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These are not the final page numbers!