Iridium-catalyzed enantioselective hydrogenation of terminal alkenes

Article abstract of DOI:10.1002/adsc.200404256

Iridium complexes derived from chiral P,N ligands are efficient catalysts for the enantioselective hydrogenation of 2-aryl-substituted terminal alkenes. Using 0.1-1 mol % of catalyst at room temperature and ambient hydrogen pressure, high enantioselectivi

Full text of DOI:10.1002/adsc.200404256

FULL PAPERS
Iridium-Catalyzed Enantioselective Hydrogenation of Terminal
Alkenes
Steven McIntyre, Esther Hçrmann, Frederik Menges, Sebastian P. Smidt,
Andreas Pfaltz*
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax: (þ41)-61-267-1103. e-mail: andreas.pfaltz@unibas.ch
Received: August 13, 2004; Accepted: November 17, 2004
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Iridium complexes derived from chiral P,N phinite-oxazoline ligand derived from threonine (Ir-
ligands are efficient catalysts for the enantioselective ThrePHOX). In contrast to the hydrogenation of tri-
hydrogenation of 2-aryl-substituted terminal alkenes. substituted alkenes, a strong pressure effect was ob-
Using 0.1–1 mol % of catalyst at room temperature served for this class of substrates. Lowering the hydro-
and ambient hydrogen pressure, high enantioselectiv- gen pressure from 50 to 1 bar resulted in a strong in-
ities (88–94% ee), full conversions after short reac- crease of the ee values.
tion times and essentially quantitative yields were ob-
tained for a range of differently substituted 2-arylal-
kenes. Among six iridium complexes that were tested, Keywords: alkenes; asymmetric hydrogenation; iridi-
the most selective catalyst was a complex with a phos- um; oxazolines; P,N ligands
Introduction
ilarly high enantioselectivities. Using chiral bis(cyclo-
pentadienyl)samarium complexes, Marks and cowork-
Iridium complexes with chiral P,N ligands are efficient ers obtained 64% ee at 258C and 96% ee at ꢀ788C in
catalysts for the enantioselective hydrogenation of un- the hydrogenation of 2-phenylbut-1-ene.[12] Noyori
functionalized alkenes.[1,2] In this respect they clearly et al.[13] examined a ruthenium complex containing
distinguish themselves from chiral rhodium and rutheni- Me-DuPhos as the chiral ligand in the hydrogenation
um catalysts, which only perform well with substrates of a series of 2-arylbut-2-enes 7b–g (Scheme 1). Under
¼
bearing a polar coordinating group next to the C C basic conditions in isopropyl alcohol, containing 0.04 to
bond.[3–5] Extensive screening of different P,N ligands 0.5 mol % of catalyst and 0.8 to 10 mol % of t-BuOK,
led to a set of catalysts that gave excellent enantioselec- the ee values ranged between 81 and 89% with conver-
tivities and high turnover numbers in the hydrogenation sions between 81–93%.
of various functionalized and unfunctionalized, acyclic
Based on the promising results obtained with Ir-Ser-
and cyclic trisubstituted olefins. [2,6–11] Typical examples PHOX catalysts, we decided to carry out a more com-
are the phosphinooxazoline (PHOX) complex Ir-1,[6] prehensive study on the hydrogenation of terminal ole-
threonine-derived phosphinite complexes Ir-2, Ir-3 and fins using the Ir catalysts shown in Figure 1.
Ir-4 (ThrePHOX),[10] the serine-derived phosphinite
complex Ir-5 (SerPHOX),[9] and the SimplePHOX com-
plex Ir-6[11] (Figure 1).
Results and Discussion
With the terminal alkene 7a (Scheme 1) only low to
moderate enantioselectivities were obtained under Ir complexes Ir-1–Ir-6 were tested as catalysts in the hy-
standard conditions (20–50 bar H2, CH2Cl2, 238C). drogenation of seven differently substituted 2-arylbut-
However, the ee was found to increase strongly when 1-enes 7a–g (Scheme 1). Unsubstituted 2-phenylbut-1-
the hydrogen pressure was lowered, contrasting obser- ene was not included in this series because no reliable
vations with trisubstituted olefins, which showed only analytical method for determining the ee of the product
very small ee variations between 5 and 100 bar.[9a] In was available. To compare the influence of hydrogen
the hydrogenation of 7a at 1 bar hydrogen pressure the pressure and temperature on the individual catalysts,
ee approached 90% with Ir-SerPHOX catalysts.[9a] three sets of reaction conditions were applied: 50 bar/
Only two other catalyst systems are known that give sim- 238C, 1 bar/238C, 1 bar/08C. The high pressure reactions
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Ir-Catalyzed Enantioselective Hydrogenation of Terminal Alkenes
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in the hydrogenation of substrates 7a–g (Table 1). Upon
lowering the hydrogen pressure from 50 bar to ambient
pressure, the enantiomeric excesses increase from 54–
62% to 88–94%. The highest enantioselectivity (94%
ee) is obtained with the electron-rich alkene 7a, whereas
the electron-poor alkene 7c gives only 88% ee. How-
ever, overall no clear trend reflecting electronic effects
of the substituents in the aryl ring is observed. Lowering
the reaction temperature to 08C results in a noticeable
decrease of enantioselectivity, especially for substrates
7a, 7c and 7 g. Thus, among the conditions tested,
room temperature and ambient pressure seem to be
ideal for this class of substrates.
Complex Ir-3 with a diphenyl- instead of a dicyclohex-
ylphosphinite group is distinctly less selective, especially
for alkenes 7c–g (Table 2). Again, hydrogenations at 1
bar give much higher enantioselectivities than those car-
ried out at elevated hydrogen pressure. In this case, no
clear trend is observed when the temperature is lowered
to 08C.
Figure 2 summarizes the results obtained in the hydro-
genation of substrate 7a with catalysts Ir-1 to Ir-6. Addi-
tional results for substrates 7b–g are listed in the Sup-
porting Information. In all cases, the enantioselectivity
increased strongly when the pressure was lowered
from 50 to 1 bar. With few exceptions, higher enantio-
meric excesses were observed at room temperature as
compared to 08C. Clearly, complex Ir-2 with a dicyclo-
hexylphosphinite ligand is the most selective catalyst.
In general, threonine-derived ThrePHOX ligands (Ir-
2, Ir-3, Ir-4) and analogous serine-derived SerPHOX li-
Figure 1. Iridium complexes with PHOX (Ir-1), ThrePHOX
(Ir-2, Ir-3, Ir-4), SerPHOX (Ir-5), and SimplePHOX ligands
ꢀ
(Ir-6). The counterion is BArF
.
were run under standard conditions with 1 mol % of cat- gands (Ir-5) are better suited for this substrate class than
alyst for 2 h, according to the screening protocol for tri- PHOX (Ir-1) or SimplePHOX ligands (Ir-6). While for
substituted alkenes. However, further experiments the screening experiments, 1 mol % of catalyst was
showed that full conversion can be reached within used, in hydrogenations at a preparative scale the
10 min or less. To speed up the screening process, often same enantioselectivity and full conversion was ob-
four reactions were run in a single autoclave equipped tained with 0.1 mol % catalyst loading.
with four glass vials, each containing a magnetic stir
The common solvent for Ir-catalyzed hydrogenations
bar. The results proved to be reproducible and consis- is dichloromethane.[2,14] 1,2-Dichloroethane (DCE) and
tent with data obtained from screening reactions in sep- toluene can be used as well, whereas more strongly coor-
arate autoclaves.
dinating solvents deactivate the catalyst. Solvent effects
Complex Ir-2 with a dicyclohexylphosphinite ligand were examined with the best catalyst for terminal al-
from the ThrePHOX series is the most selective catalyst kenes, Ir-2, and with Ir-PHOX complex Ir-1 using alkene
7a as substrate (Table 3). In all three solvents the ee lev-
els were similar. Interestingly, the enantioselectivity of
catalyst Ir-2 in DCE and toluene increased when the
temperature was lowered to 08C, whereas the opposite
trend was observed in dichloromethane. Catalyst Ir-1
showed a more pronounced temperature effect resulting
in a substantial increase of enantioselectivity when the
temperature was raised from 08C to 258C. With this cat-
alyst the ee was significantly higher in DCE than in di-
chloromethane. The results show that toluene is a viable
alternative to halogenated solvents.
In order toaccelerate catalystscreening, aprotocol for
simultaneous hydrogenation of a mixture of substrates
Scheme 1.
in the same solution was developed.[15] Hydrogenation
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Table 1. Hydrogenation of substrates 7a–g with catalyst Ir-2 using three different reaction conditions.
Entry
Complex[a]
Substrate
p [bar]
T [ 8C]
Time [min]
Conv.[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
7a
7a
7a
7b
7b
7b
7c
7c
7c
7d
7d
7d
7e
7e
7e
7f
50
1
1
50
1
1
50
1
1
50
1
1
50
1
1
50
1
1
50
1
1
25
25
0
25
25
0
25
25
0
25
25
0
25
25
0
25
25
0
25
25
0
120
30
30
120
30
30
120
30
30
120
30
30
120
30
30
120
30
30
120
30
30
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
58
94
90
56
91
89
54
88
84
59
89
88
62
93
90
61
92
91
59
94
87
7f
7f
7g
7g
7g
[a]
ꢀ
1 mol % of Ir-complex Ir-2. Anion: BArF
Determined by GC.
.
[b]
[c]
Determined by HPLC (see refs.[6,7]).
Figure 2. ee values obtained in the hydrogenation of substrate 7a with catalysts Ir-1 to Ir-6; reaction conditions: (a) 50 bar,
258C; (b) 1 bar, 258C; (c) 1 bar, 08C.
of an equimolar mixture of alkenes 7a, 7c, 7e, and 7f with 8e, and 8f (Figure 3). Simultaneous screening of catalyst
catalyst Ir-2 at ambient hydrogen pressure resulted in mixtures can be problematic if the different substrates
full conversion after 30 min. GC analysis of the product or products interact with each other. However, the ee
mixture on a chiral column showed well resolved peaks values determined from this chromatogram were identi-
for all enantiomers of the hydrogenated products 8a, 8c, cal to those obtained in reactions performed with a sin-
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Figure 3. Determination of the ee values of products 8a, 8c, 8e, and 8f from hydrogenation of a mixture of substrates with cat-
alyst Ir-2, using gas chromatography on a chiral column. Conditions: g-CD TFA, 30 m, 100 kPa H2, 608C/30 min/0.58C·minꢀ1
778C/0 min/208C·minꢀ1/1808C/10 min.
/
Table 2. Hydrogenation of substrates 7a–g with catalyst Ir-3 using three different reaction conditions.
Entry
Complex[a]
Substrate
p [bar]
T [ 8C]
Time [min]
Conv.[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
7a
7a
7a
7b
7b
7b
7c
7c
7c
7d
7d
7d
7e
7e
7e
7f
50
1
1
50
1
1
50
1
1
50
1
1
50
1
1
50
1
1
50
1
1
25
25
0
25
25
0
25
25
0
25
25
0
25
25
0
25
25
0
25
25
0
60
30
30
60
30
30
60
30
30
60
30
30
60
30
30
60
30
30
60
30
30
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
71
90
89
73
88
86
46
59
64
54
73
69
55
71
68
60
75
76
62
76
74
7f
7f
7g
7g
7g
[a]
–
1 mol% of Ir-complex Ir-3. Anion: BArF
Determined by GC.
.
[b]
[c]
Determined by HPLC (see refs.[6,7]).
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tionalized terminal alkenes, the pressure effect was very
weak in this case (Entries 3 and 4). Interestingly, cata-
lysts Ir-1 and Ir-6 gave higher enantioselectivities at
higher pressure, contrasting the results obtained with al-
kenes 7a–g. The enantiomeric excess achieved with cat-
gle substrate. Obviously, the presence of additional sub- alyst Ir-2 is comparable to the ee value reported for the
strates does not affect the outcome of the four individual synthesis of alcohol 10 by zirconocene-catalyzed asym-
reactions, so this protocol can be used as a fast and reli- metric methylalumination of 4-chlorostyrene (90%
able screening method.
ee).[17] However, the iridium-catalyzed hydrogenation
To examine the influence of a polar neighboring group is a more efficient, faster process requiring less catalyst.
which can coordinate to the catalyst, allylic alcohol 9 was
hydrogenated using four different Ir complexes (Ta-
ble 4). Derivatives of the hydrogenation product 2-phe- Conclusion
nylpropanol (10) are frequently used as components of
fragrance mixtures.[16] Again, complex Ir-2 proved to Iridium complexes derived from chiral phosphinite-ox-
be the most selective catalyst, giving rise to 88% ee at azoline ligands, especially the ThrePHOX complex Ir-
08C and 1 bar hydrogen pressure. Compared to unfunc- 2, are efficient catalysts for the hydrogenation of 2-
Table 3. Solvent effects on the enantioselective hydrogenation of 7a with catalysts Ir-1 and Ir-2.
Entry
Complex[a]
T [ 8C]
Solvent
Conv.[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
0
25
0
25
40
0
25
40
CH2Cl2
CH2Cl2
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
Toluene
>99
>99
>99
>99
>99
>99
>99
>99
90
94
93
91
87
93
90
90
Toluene
Toluene
9
0
25
0
25
40
CH2Cl2
>99
>99
>99
>99
>99
18
61
43
73
76
10
11
12
13
CH2Cl2
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
[a]
ꢀ
1 mol % of Ir-complex. Anion: BArF
.
[b]
[c]
Reaction time¼30 min. Determined by GC.
Determined by HPLC (see refs.[6,7]).
Table 4. Hydrogenation of terminal allylic alcohol 9.
Entry
Complex[a]
p [bar]
T [ 8C]
Time [min]
Conv.[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
9
Ir-1
Ir-1
Ir-2
Ir-2
Ir-2
Ir-5
Ir-5
Ir-6
Ir-6
50
1
50
1
1
50
1
25
25
25
25
0
25
25
25
25
120
120
120
120
120
120
120
120
120
>99
54
78
62
81
83
88
51
50
77
66
>99
>99
>99
>99
>99
>99
51
50
1
[a]
ꢀ
1 mol % of Ir-complex. Anion: BArF
Determined by GC.
.
[b]
[c]
Determined by HPLC (see refs.[6,7]).
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lute, over molecular sieves, H2O¼0.005%) was prepared under
argon in a 15 mL Schlenk flask. The reaction mixture was stir-
red for 30 min with slow bubbling of hydrogen gas through the
solution, introduced through a stainless-steel needle. The tem-
perature was either 258C or 08C and kept constant by a water
or ice bath. Work-up and analyses were performed as described
for the high pressure reactions.
aryl-substituted terminal alkenes. With enantiomeric
excesses of 88–94%, the enantioselectivities are compa-
rable to the best values reported so far for this class of
substrates. In contrast to the bis(cyclopentadienyl)sa-
marium complex used by Marks that requires very low
temperature for high enantioselectivity, Ir-catalyzed hy-
drogenation gives optimum results at room tempera-
ture. In addition, full conversion is obtained under neu-
tral and mild conditions after short reaction times,
whereas in the Ru-catalyzed hydrogenations developed
by Noyori et al.,[13] a 20-fold excess of potassium tert-but-
oxide with respect to the catalyst was added to the reac-
tion mixture. Moreover, the Ir complexes, used as preca-
talysts, are air- and moisture-stable and easy to handle.
In summary, Ir-catalyzed hydrogenation provides an ef-
ficient, practical enantioselective route to chiral a-
methyl-substituted benzylic compounds.
Hydrogenation on a Preparative Scale
A solution of 7a (1.005 g, 6.19 mmol) in 60 mL of dichlorome-
thane (0.1 M) was mixed with 0.1 mol % (10.7 mg) Ir-2 under
nitrogen. The reaction flask was connected to a gas burette
and purged with hydrogen gas. Hydrogenation was then per-
formed at ambient temperature and pressure with magnetic
stirring. After 2 h, full conversion was obtained as determined
by gas consumption and confirmed by GC analysis. The solvent
was removed under vacuum (40 mbar/258C) and the crude
product was purified by filtration through a silica gel column
(h¼4 cm, ø¼2 cm) with 100 mL of pentane. Pentane was re-
moved under vacuum at the same pressure and temperature
to give 8a as a colorless oil; yield: 993 mg (98%), 94% ee.
Experimental Section
Materials
Acknowledgements
Chiral ligands 1–6 and their corresponding iridium complexes
Ir-1 to Ir-6 were prepared according to literature proce-
dures.[6,7,9–11] Syntheses and characterization of compounds
7a–g, 8a–g, and 9 are described in the Supporting Information.
A comprehensive documentation of catalytic results obtained
with Ir-1, Ir-4, Ir-5, and Ir-6 are given in Tables S1–S4 in the
Supporting Information.
F. M. thanks the Fonds der chemischen Industrie, Frankfurt, and
the German Federal Ministry for Science and Technology
´
(BMBF) for a Kekule Fellowship. S. P. S. thanks the German
Academic Exchange Service (DAAD) and the Gottlieb Daim-
ler- and Carl Benz-Foundation for Ph. D. fellowships. Financial
support by the Swiss National Science Foundation, the Federal
Commission for Technology and Innovation (KTI Project No.
5189.2 KTS), and Solvias AG is gratefully acknowledged.
Screening Conditions for Catalytic Hydrogenations at
Elevated Pressure
A solution of 0.1 mmol substrate and 1 mol % iridium pre-cat-
alyst in 0.5 mL of dry dichloromethane (Fluka puriss., absolute,
over molecular sieves, H2O¼0.005%) was stirred in a high-
pressure autoclave under 50 bar hydrogen gas for two hours.
Stirring was done with magnetic stir bars at 700 minꢀ1. All re-
actions were performed at room temperature. The reactions
were generally set up in the air. Either one reaction was run
at a time in a 35 mL glass-insert, or four reactions were run
in one autoclave in 2 mL glass vials that were individually stir-
red. Test reactions gave consistent results with both methods
and no gas-phase diffusion of the more volatile substrates
from one vial to another was observed. Work-up consisted in
evaporating the solvent in a stream of nitrogen or argon and ex-
traction of the hydrogenation product with 3 mL of heptanes
(HPLC quality). After filtration through a syringe filter
(0.2 mm, Macherey-Nagel CHROMAFIL type O-20/15, for or-
ganic solvents), these solutions were directly used for GC and
HPLC analyses.
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