An additional coordination group leads to extremely efficient chiral iridium catalysts for asymmetric hydrogenation of ketones

Article abstract of DOI:10.1002/anie.201102710

What a turnover! An efficient chiral iridium catalyst that bears a tridentate spiro aminophosphine ligand catalyzes the asymmetric hydrogenation of ketones with excellent enantioselectivities (up to 99.9 % ee) and extremely high turnover numbers (TONs; as high as 4 550 000). Copyright

Full text of DOI:10.1002/anie.201102710

DOI: 10.1002/anie.201102710
Asymmetric Hydrogenation
An Additional Coordination Group Leads to Extremely Efficient
Chiral Iridium Catalysts for Asymmetric Hydrogenation of Ketones**
Jian-Hua Xie,* Xiao-Yan Liu, Jian-Bo Xie, Li-Xin Wang, and Qi-Lin Zhou*
The production of enantiopure chiral compounds is important
for pharmaceutical and agrochemical industries because
enantiomers can exhibit distinct biological activities. There-
fore, processes that directly produce the desired enantiomer
are desirable. First reported by Knowles, Horner et al. in
1968,[1] catalytic asymmetric hydrogenation of unsaturated
compounds such as olefins, ketones, and imines is one of the
most commonly used methods for producing enantiopure
chiral compounds.[2] Great progress has been made in this
field, and many chiral catalysts are developed for a wide range
of unsaturated substrates.
asymmetric hydrogenations.[6] However, these catalysts are
easily deactivated by irreversible formation of inactive dimers
or trimers under the hydrogenation conditions, and this
deactivation prevents the achievement of extremely high
TONs.[2b] To overcome this limitation, investigators have
employed several strategies, including immobilization, den-
drimerization, the use of a bulky counteranion, and the
introduction of a bulky or rigid ligand.[7] Although these
strategies substantially increased the stability and/or reactiv-
ity of chiral Ir/P–N catalysts, the efficiencies were still below
the level required for practical use.
It is noteworthy that some of these synthetic chiral
catalysts, which are much smaller and simpler than enzymes,
exhibit activities and selectivities comparable to those of
enzymes: in some cases, one molecule of catalyst can produce
millions of new molecules enantioselectively. For example,
the diphosphine/diamine ruthenium catalyst reported by
Noyori et al.[3] and the iridium ferrocenyl catalyst Ir-(R,S)-
Xyliphos developed by a team from Novartis[4] (Scheme 1)
We recently developed new chiral iridium catalysts that
bear a spiro aminophosphine ligand (SpiroAP; 1, Scheme 2)
and efficiently catalyze the asymmetric hydrogenation of
aromatic and a,b-unsaturated ketones under mild condi-
tions.[8] However, these catalysts also tend to lose their
activity under hydrogenation conditions.[8b] We attributed the
deactivation to the formation of an inactive iridium dihydride
complex with two SpiroAP ligands. To inhibit the coordina-
tion of a second SpiroAP ligand to the iridium atom of
the catalyst, we introduced an additional coordination
group to the SpiroAP, making it a tridentate ligand. This
modification led to a novel chiral spiro iridium catalyst
with exceptionally high stability and activity for ketone
hydrogenation. Herein, we report the synthesis, charac-
terization, and application of new iridium catalysts with
tridentate spiro ligands, SpiroPAP (2), to the hydro-
genation of simple ketones. The new catalysts afforded
chiral alcohols in up to 99.9% ee and with TONs as high
as 4550000.
Scheme 1. Examples of exceptionally efficient chiral catalysts.
We chose a pyridine moiety as the additional
coordination group because the pyridine ring can be easily
modified and has suitable coordination ability in many
iridium catalysts.[9] Starting from 1, SpiroPAP ligands 2 were
conveniently synthesized in high yields (82–99%) by means of
have turnover numbers (TON, molar ratio of converted
substrate to catalyst) as high as 1000000 for the hydro-
genation of ketones and imines.[5] However, chiral catalysts
with TONs over a million are rare, and most of the reported
chiral catalysts have TONs lower than 1000 and are unable to
obtain applications in industry.
Chiral iridium complexes with phosphorus–nitrogen
ligands are among the most commonly used catalysts in
[*] Prof. J.-H. Xie, X.-Y. Liu, J.-B. Xie, Prof. L.-X. Wang, Prof. Q.-L. Zhou
State Key Laboratory and Institute of Elemento-organic Chemistry
Nankai University, Tianjin 300071 (China)
E-mail: jhxie@nankai.edu.cn
qlzhou@nankai.edu.cn
[**] We thank the National Natural Science Foundation of China, the
National Basic Research Program of China (2010CB833300,
2011CB808600) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102710.
Scheme 2. Synthesis of SpiroPAP ligands.
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Table 1: Optimizing the reaction conditions of the asymmetric hydro-
a one-step procedure involving reaction with picolinalde-
hydes (3) in dichloroethane (DCE) in the presence of
NaBH(OAc)3 as a reducing agent (Scheme 2).
genation of acetophenone.[a]
The coordination of ligands 2 to the iridium atom was
verified by analysis of the single crystal structure of the
complex [IrH2((R)-2c)Cl][10] (Figure 1) obtained from the
Entry
Ligand
Solvent
t
Conv [%][b]
Ee [%][c]
1
2
3
4
5
6
7
8
(R)-1c
(R)-2c
(R)-2c
(R)-2c
(R)-2c
(R)-2c
(R)-2a
(R)-2b
(R)-2d
(R)-2e
(R)-2 f
(R)-2g
(R)-2h
(R)-2g
(R)-2g
(R)-2g
(R)-2g
nPrOH
nPrOH
MeOH
EtOH
iPrOH
Toluene
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
10 min
1 h
3 min
20 min
4 h
16 h
1 h
1 h
20 min
25 min
18 h
<20 min
45 min
5 h
6 h
30 h
15 days
100
100
>99
100
100
100
100
100
100
100
100
100
100
100
100
100
91
92 (S)
96 (S)
91 (S)
97 (S)
86 (S)
67 (S)
69 (S)
76 (S)
96 (S)
95 (S)
85 (S)
98 (S)
98 (S)
90 (S)
92 (S)
98 (S)
98 (S)
9
10
11
12
13
14[d]
15[e]
16[f]
17[g]
Figure 1. ORTEP diagram of [IrH2((R)-2c)Cl]. Thermal ellipsoids set at
30% probability. Selected bond lengths [ꢀ] and angles [8]: Ir1-P1 2.224,
Ir1-N1 2.228, Ir1-N2 2.033, Ir1-H1 1.403, Ir1-H2 1.405; P1-Ir1-N1
99.98(15), P1-Ir1-N2 178.7(4), N1-Ir1-N2 81.30(4), N1-Ir1-H1
105.00(3), N1-Ir1-H2 166.00(3), H1-Ir1-H2 86.00(4), P1-Ir1-N1-N2
À179.87.
[a] Reaction conditions: 7.5 mmol scale, [substrate]=2.1m, 0.01 mol%
[{Ir(cod)Cl}2], 0.022 mol% ligand, [KOtBu]=0.02m , solvent volume=
2.0 mL, room temperature (25–308C). [b] Determined by GC. [c] Deter-
mined by GC on a Supelco chiral b-dex-225 solid phase. [d] 1 atm H2.
[e] S/C=100000, 50 atm H2 (initial). [f] S/C=1000000, 50 atm H2
(initial). [g] S/C=5000000, 100–60 atm H2.
reaction of (R)-2c with [{Ir(cod)Cl}2] (cod = cyclooctadiene)
in MeOH under hydrogen. In the crystal structure of
[IrH2((R)-2c)Cl], ligand (R)-2c was coordinated to the
iridium atom by means of one phosphorus atom and two
nitrogen atoms by a conformationally restricted eight-mem-
bered ring and a five-membered heterometal ring. The newly
introduced sp2 nitrogen atom of the pyridine ring was
coordinated to the iridium atom in a trans orientation relative
to the phosphorus atom (P1–Ir1–N2, 178.78) and was located
in the plane defined by the iridium, phosphorus, and sp3
nitrogen atoms (P1–Ir1–N1–N2 torsion angle, À179.878).
This structural characteristic indicates that [IrH2((R)-2c)Cl]
for the most part retained the original core structural
characteristics of the Ir–SpiroAP catalysts, despite the
introduction of the pyridine moiety.[8b] However, the bite
angle P–Ir–N(sp3) (99.988) in [IrH2((R)-2c)Cl] was clearly
larger than that in [Ir((R)-1c)(cod)]BF4 (91.798). The
increased angle brought the Ir atom, the reaction center of
the catalyst, closer to the spirobiindane backbone and created
a chiral environment around the Ir atom that permitted more
efficient catalysis. The fact that no dimer or trimer formation
was observed in the preparation of [IrH2((R)-2c)Cl] at a
hydrogen pressure of 1 atm shows that the iridium catalyst
was highly stabilized by the introduction of the pyridine
moiety.
was the best solvent for Ir-(R)-2c, and the reaction was
completed within 20 min, giving (S)-5a in 97% ee (entry 4).
Ligand screening revealed that the substituents on the P-
phenyl rings and on the pyridine ring of the ligand markedly
affected the activity and enantioselectivity of the catalyst
(entries 7–13); the ligand (R)-2g, which has 3,5-tert-butyl
groups on the P-phenyl rings and a 3-methyl group on the
pyridine ring, gave the best result (98% ee, less than 20 min,
entry 12). As we expected, Ir-(R)-2g was very stable and
active. When the catalyst loading was lowered to
0.0001 mol% (S/C = 1000000), the hydrogenation product
(S)-5a was still obtained in 98% ee with 100% conversion
within 30 h at room temperature under an initial hydrogen
pressure of 50 atm (the final hydrogen pressure was about
20 atm). When the catalyst loading was further lowered to
0.00002 mol%
(S/C=5000000), the reaction still proceeded well under 100–
60 atm of H2 pressure and provided (S)-5a in 98% ee with
91% conversion within 15 days (TON = 4550000, turnover
frequency = 12600 hÀ1).
The preliminary hydrogenation was carried out under
conditions previously optimized for the reaction catalyzed by
Ir-(R)-1c (substrate/catalyst, S/C = 5000, 10 atm H2, 25–
308C).[8b] Hydrogenation of the standard substrate, acetophe-
none (4a), over Ir-(R)-2c generated in situ from 0.01 mol%
[{Ir(cod)Cl}2] and 0.022 mol% (R)-2c afforded (S)-5a within
1 h with 100% conversion and 96% ee (Table 1, entry 2). This
enantioselectivity was better than that obtained with Ir-(R)-
1c (92% ee, entry 1). Solvent experiments showed that EtOH
A wide range of ketones were hydrogenated over Ir-(R)-
2g under the standard reaction conditions (Table 2). All the
tested aromatic ketones (4a–o) underwent hydrogenation
smoothly to afford the corresponding chiral alcohols (5a–o)
in high yields (from 96 to > 99%) and excellent enantiose-
lectivities (96–99.9% ee) (Table 2, entries 1–15). We were
pleased to find that 3,5-bis-(trifluoromethyl)acetophenone
(4o) was hydrogenated to the corresponding alcohol (5o)
with an ee as high as 99.9% (entry 15). When the catalyst
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Angew. Chem. Int. Ed. 2011, 50, 7329 –7332

Table 2: Asymmetric hydrogenation of ketones with Ir-(R)-2g.[a]
(S/C = 10000) without diminishment of the enantioselectivity
of the reaction (Scheme 3). This result provides an efficient
approach to the synthesis of optically active 3-n-butylphtha-
lide.[15] However, like catalyst Ir-(R)-1c,[8b] Ir-(R)-2g was less
efficient for the asymmetric hydrogenation of aliphatic
ketones such as cyclohexyl methyl ketone (4q, entry 17).
In conclusion, we developed a new strategy for inhibiting
the deactivation of chiral iridium catalysts by introducing an
additional coordination group into the catalysts. This strategy
led to the discovery of a highly active and enantioselective
chiral iridium catalyst for ketone hydrogenation. With iridium
Entry R1
R2
Prod
t
Yield [%][b] Ee [%][c]
1
2
3
4
5
6
7
8
C6H5
C6H5
4-MeC6H4
4-MeOC6H4
4-ClC6H4
Me 5a
Et 5b
20 min >99
40 min >99
50 min >99
40 min 98
40 min 96
40 min 98
40 min 96
50 min 99
50 min 98
98 (S)
96 (S)
98 (S)
98 (S)
97 (S)
96 (S)
98 (S)
98 (S)
98 (S)
99.3 (S)
99.6 (S)
99 (S)
98 (S)
96 (S)
99.9 (S)
99 (S)
88 (S)
Me 5c
Me 5d
Me 5e
Me 5 f
Me 5g
Me 5h
Me 5i
Me 5j
Me 5k
Me 5l
Me 5m
Me 5n
Me 5o
À À
catalyst Ir-(R)-2g, which has a tridentate spiro P N N ligand,
4-BrC6H4
3-MeC6H4
3-MeOC6H4
3-BrC6H4
2-MeC6H4
2-MeOC6H4
2-ClC6H4
2-BrC6H4
2-naphthyl
3,5-(CF3)2C6H3
the efficiency of the asymmetric hydrogenation has reached a
new level.
9
10
11
12
13
14
15
16[d]
17[e]
3 h
99
40 min 99
35 min 97
Experimental Section
General procedure for asymmetric hydrogenation of ketones at S/C =
5000: The catalyst precursor [{Ir(cod)Cl}2] (0.5 mg, 0.75 mmol), ligand
(R)-2g (1.2 mg, 1.6 mmol), and anhydrous EtOH (2 mL) were added
under nitrogen to a hydrogenation vessel (20 mL). The mixture was
stirred for 1.0 h at 25–308C to give a clear yellow solution. The vessel
was then placed in an autoclave and purged with hydrogen by
pressurizing to 1 atm and releasing the pressure. This procedure was
repeated three times and the solution was stirred for 1.0 h under 1 atm
of H2. After releasing the pressure, ketone (7.5 mmol) and a solution
of tBuOK in EtOH (0.134 mmolmLÀ1, 0.5 mL, 0.067 mmol) were
added through the injection port. The autoclave was then pressurized
to 10 atm of H2 and the reaction mixture was stirred at room
temperature (25–308C) until no obvious hydrogen pressure drop was
observed. After releasing the hydrogen pressure, the reaction mixture
was filtered through a short silica gel column, and the filtrate was
analyzed by GC to determine the conversion. The solvent in the
filtrate was removed to determine the yield. The enantiomeric excess
of the product was determined by GC or HPLC on a chiral stationary
phase.
4 h
97
30 min 97
1.5 h
1 h
4 h
98
99
98
2-MeOCOC6H4 Bu 5p
cyclohexyl Me 5q
[a] Reaction conditions were the same as those listed in Table 1, entry 12.
[b] Yield of isolated product. [c] Determined by GC or HPLC on a chiral
stationary phase (see the Supporting Information). [d] The product was
(S)-3-butylisobenzofuran-1(3H)-one. [e] S/C=1000.
loading was reduced to 0.001 mol% (S/C = 100000), hydro-
genation of 4o still proceeded well to give alcohol 5o in 98%
yield and 99% ee under 50 atm H2 (initial). This reaction
provided a highly efficient method for the synthesis of (R)-5o,
an important chiral intermediate for a number of pharma-
ceutically interesting targets such as the NK-1 receptor
antagonist aprepitant (Scheme 3).[11] The ee for this reaction
was better than that obtained by a team from Solvias using a
Ru-(phosphinoferrocenyl)oxazoline complex as the catalyst
(94.3% ee at S/C = 50000).[12] The hydrogenation of ethyl 2-
pentanoylbenzoate (4p) provided direct access to optically
active 3-n-butylphthalide (5p),[13] which is a medical agent for
the treatment of brain-related neurological diseases such as
ischemic stroke.[14] When Ir-(R)-2g was used to catalyze the
hydrogenation of 4p, the corresponding 3-n-butylphthalide
((S)-5p) was obtained in 98% yield and 99% ee (entry 16).
The catalyst loading could be further lowered to 0.01 mol%
Received: April 19, 2011
Published online: July 12, 2011
Keywords: asymmetric catalysis · chiral alcohols ·
.
hydrogenation · iridium · ketones
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hydrogenation of ethyl 2-pentanoylbenzoate was reported: using
catalyst Ru–TsDBuPEN, 92% yield, 98% ee at S/C = 200
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