Iron catalyzed asymmetric hydrogenation of ketones

Article abstract of DOI:10.1021/ja5003636

Chiral molecules, such as alcohols, are vital for the manufacturing of fine chemicals, pharmaceuticals, agrochemicals, fragrances, and novel materials. These molecules need to be produced in high yield and high optical purity and preferentially catalytically. Among all the asymmetric catalytic reactions, asymmetric hydrogenation with H₂ (AH) is the most widely used in the industry. With few exceptions, these AH processes use catalysts based on the three critical metals, rhodium, ruthenium, and iridium. Herein we describe a simple, industrially viable iron catalyst that allows for the AH of ketones, a process currently dominated by ruthenium and rhodium catalysts. By combining a chiral, 22-membered macrocyclic ligand with the cheap, readily available Fe ₃(CO)₁₂, a wide variety of ketones have been hydrogenated under 50 bar H₂ at 45-65 C, affording highly valuable chiral alcohols with enantioselectivities approaching or surpassing those obtained with the noble metal catalysts. In contrast to AH by most noble metal catalysts, the iron-catalyzed hydrogenation appears to be heterogeneous.

Full text of DOI:10.1021/ja5003636

Article
pubs.acs.org/JACS
Iron Catalyzed Asymmetric Hydrogenation of Ketones
Yanyun Li,†,‡,§ Shenluan Yu,†,‡,§ Xiaofeng Wu,‡ Jianliang Xiao,*,‡ Weiyi Shen,† Zhenrong Dong,†
and Jingxing Gao*,†
†State Key Laboratory of Physical Chemistry of Solid Surfaces, National Engineering Laboratory for Green Chemical Productions of
Alcohols, Ethers, and Esters, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China
‡Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom
S
* Supporting Information
ABSTRACT: Chiral molecules, such as alcohols, are vital for the
manufacturing of fine chemicals, pharmaceuticals, agrochemicals,
fragrances, and novel materials. These molecules need to be
produced in high yield and high optical purity and preferentially
catalytically. Among all the asymmetric catalytic reactions,
asymmetric hydrogenation with H2 (AH) is the most widely
used in the industry. With few exceptions, these AH processes use
catalysts based on the three critical metals, rhodium, ruthenium,
and iridium. Herein we describe a simple, industrially viable iron
catalyst that allows for the AH of ketones, a process currently
dominated by ruthenium and rhodium catalysts. By combining
a chiral, 22-membered macrocyclic ligand with the cheap, readily
available Fe3(CO)12, a wide variety of ketones have been
hydrogenated under 50 bar H2 at 45−65 °C, affording highly valuable chiral alcohols with enantioselectivities approaching or
surpassing those obtained with the noble metal catalysts. In contrast to AH by most noble metal catalysts, the iron-catalyzed
hydrogenation appears to be heterogeneous.
INTRODUCTION
■
Asymmetric hydrogenation (AH) has come a long way over the
last half century, culminating with the award of the Nobel Prize
to Noyori and Knowles for their contribution to the field
in 2001. Being totally atom-economical, scalable, and robust,
AH is now universally used for the synthesis of various chiral
compounds, ranging from alcohols through amines to acids,
and accounts for more than half of all the industrial asymmetric
catalytic processes.1−4 In both academic laboratories and
industrial operations, AH reactions are catalyzed principally by
metal complexes based on rhodium, ruthenium, and iridium.
A case in point is the AH of ketones, which has been used in a
number of industrial processes ranging from kilogram to ton
scales for the synthesis of pharmaceuticals, agrochemicals,
and fragrances, where ruthenium- and rhodium-based catalysts
Figure 1. Representative iron catalysts used for hydrogenation.
currently dominate the scene.1,3,4 However, the limited
availability, risk in supply, high and volatile price, and toxicity
Hydrogenation with H2 catalyzed by achiral iron catalysts
has also been demonstrated (Figure 1).11 Notable examples
include the hydrogenation of alkenes reported by the groups
of Chirik11n and Peters,11o ketones by Casey,11p Morris,11q,r and
Milstein,11s and CO2 and nitroarenes by Beller11t,u and their
co-workers. A recurring feature of the catalysts reported is the
use of multidentate open-chain ligands, presumably echoing the
of these critical metals call for their replacement with abundant,
inexpensive, and biocommon metals, such as iron.5,6
As one of the most abundant metals on earth, iron is
inexpensive, environmentally benign, and of low toxicity, and as
such it is a fascinating alternative to the precious metals for
catalysis and sustainable chemical manufacturing.6,7 However,
iron catalysts have been significantly undeveloped compared with
other transition metals. Only in the past few years has signifi-
cant progress been witnessed in iron catalysis,7−10 including in
particular transfer hydrogenation9 and hydrosilylation.10
Received: January 13, 2014
Published: February 13, 2014
© 2014 American Chemical Society
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generally lower stability of iron complexes in comparison with
those made of the noble metals. In contrast, in most AH
reactions catalyzed by the noble metals, bidentate and to some
degree monodentate chiral phosphorus compounds are the
ligand of choice.1
Iron catalysts that are efficient for AH reactions have been
elusive, however. No iron catalysts have been known capable of
AH of olefins, and only recently has AH of imino bonds been
metal-catalyzed AH and ATH and to those attempted for AH
with iron,1−4,7−10 ligand 1 is macrocyclic, having 22 atoms
including 6 potentially coordinating N and P atoms in the ring. In
continued effort on asymmetric reduction in our laboratories,15,16
we have found that the same combination also enables highly
efficient AH of a broad range of ketones, with enantioselectivities
approaching or exceeding those achievable with the noble metal
catalysts. It is worth pointing out that over the past half century,
only a few catalysts have been shown to be effective for both AH
and ATH reactions,1v,17 and developing a “universal” catalyst that
allows the AH as well as ATH of a range of substrates remains
challenging. Ligand 1 coupled with Fe3(CO)12 fills, to a significant
degree, the gap in the area of asymmetric ketone reduction.
Reported herein are our results on the AH of ketones with this
catalyst.
reported by Beller et al. using the achiral Knolker complex in
̈
the presence of a chiral Bronsted acid.12 Concerning the AH of
ketones, there are only two iron catalysts so far, which show
appreciable activities and enantioselectivities, and in both cases
only the substrate acetophenone was examined.11q,r,13,14 In
one case, acetophenone was reduced with a chiral Fe−N2P2
complex in the presence of a base, affording 27% ee and 40%
conversion in isopropanol (iPrOH) at 50 °C under 25 atm
of H2 at a substrate/catalyst (S/C) ratio of 225 (eq 1).11q
METHODS
■
Ligand 1 can be readily accessed by condensing a phosphino-aldehyde
with chiral cyclohexyl diamine followed by reduction of the resulting
cyclic imino compound 2 with NaBH4.15
Typical Procedure for AH. A dried glassliner (20 mL) was
charged with Fe3(CO)12 (2.5 mg, 0.005 mmol) and 1 (4.0 mg,
0.005 mmol) under N2 and then loaded into an dried autoclave. After
the addition of freshly distilled MeOH (5 mL), the autoclave was
purged with H2 (1 bar) three times. The mixture was then stirred at
45 °C under 5 bar H2 for 1 h. After releasing the H2 gas in a
fumehood, KOH in MeOH (0.5 M, 0.4 mL) and acetophenone
(1 mmol) were sequentially introduced through an injection port. The
autoclave was then pressurized to 50 bar H2, and the reaction mixture
stirred at 45 °C for 5 h. After cooling down to room temperature and
subsequently releasing the H2 pressure in a fumehood, the mixture was
concentrated and purified by chromatograph on a silica-gel column
with ethyl acetate/hexane (v/v = 5:95), affording 1-phenylethanol
in 97% isolated yield. The enantioselectivity of the product was
determined by GC equipped with a chiral Chrompack Chirasil-Dex
CB column (25 m x 0.25 mm).
Procedure for Larger-Scale AH of Acetophenone. The pro-
cedure was similar to that above, using a 125 mL glassliner charged
with Fe3(CO)12 (101.0 mg, 0.2 mmol), 1 (160.0 mg, 0.2 mmol), and
MeOH (50 mL). Following stirring for 1 h at 45 °C under 5 bar H2, a
MeOH solution of KOH (0.5 M, 16 mL) and acetophenone (12.00 g,
100.0 mmol) were introduced. The mixture was then stirred for 12 h
at 45 °C under 50 bar H2 pressure. Purification by chromatograph on
a silica-gel column with ethyl acetate/hexane (v/v = 5:95) afforded
the corresponding chiral alcohol in 98% isolated yield (11.93 g) with
96% ee.
Procedure for AH of Acetophenone in the Presence of a
Poison Additive. A dried glassliner (20 mL) was charged with
Fe3(CO)12 (5 mg, 0.01 mmol) and 1 (8.0 mg, 0.01 mmol) under N2
and then loaded into an dried autoclave. After the addition of freshly
distilled MeOH (8 mL), the autoclave was purged with H2 (1 bar)
three times. The mixture was then stirred at 45 °C under 5 bar H2 for
1 h. After releasing the H2 gas in a fumehood, KOH in MeOH (0.5 M,
0.8 mL), acetophenone (1 mmol) and an additive (triphenylphos-
phine, 1,10-phenanthroline, or mercury, 0.001−0.03 mmol) (see
Table 6) were sequentially introduced through an injection port. The
autoclave was then pressurized to 50 bar H2, and the reaction mixture
stirred at 45 °C for a certain period of time (see Table 6). After
cooling down to room temperature and subsequently releasing the H2
pressure in a fume hood, the sample was analyzed as above. In the case
of using mercury, the sample was carefully taken at the top of the
reaction mixture, the rest of which was quenched with sulfur and
collected in a special bottle for disposal.
In the other, a Knolker type complex modified with a chiral
̈
phosphoramidite ligand catalyzed the AH under UV radiation,
furnishing 1-phenylethanol in 31% ee and 90% yield under
10 bar of H2 at an S/C ratio of 10 (eq 2).13 Clearly, it remains
a grand challenge to develop an iron catalyst that is capable of
synthetically viable AH reactions.
One of our groups recently reported a novel chiral ligand
(R,R,R,R)-1, which, when combined with a readily available
iron carbonyl compound Fe3(CO)12, displays excellent enantio-
selectivities in the asymmetric transfer hydrogenation (ATH)
of various ketones with iPrOH as the reductant (eq 3).15
In contrast to almost all the chiral ligands found in the noble
RESULTS AND DISCUSSION
■
Optimization of AH Conditions. We first examined the
AH of the benchmark substrate acetophenone by combining
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to indicate that the formation of active catalyst species, for
example, iron hydrides, depends on the basicity of the reaction
mixture. The accelerating effect of a base on the reaction rate
of AH with precious metal catalysts has been noted in a number
of cases;18 however, base-free conditions have also been
demonstrated.11a,19 Further optimization revealed that lowering
the reaction temperature did not improve the ee but significantly
reduced the AH rate (Table 1, entry 16), and ligand 2 was
ineffective in the AH (Table 1, entry 17), hinting that the NH
group of 1 may play an important role in the reaction, as in the
case of the Noyori metal−ligand bifunctional catalysts, for
example, Ru(diphosphine)(diamine).1v,3a
Table 1. Screening of Catalysts and Conditions for the AH of
Acetophenone
a
b
b
]
]
Entry
Iron source
Base
Conv (%)[
Ee (%)[
1
2
3
4
5
6
7
8
9
[Et3NH][HFe3(CO)11]
[PPN][HFe3(CO)11]
[CpFe(CO)2]2
[CpFe(CO)2I]
Fe(CO)4(PPh3)2
trans-Fe(CO)3(PPh3)2
Fe(acac)3
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
None
KOH
tBuOK
NaOH
K2CO3
KOH
KOH
<1
<1
none
<1
AH of Aryl Ketones. With the optimized reaction condi-
tions in hand, we then applied the catalytic system to the
reduction of a wide range of ketones. As shown in Table 2,
various aryl methyl ketones were reduced with 1/Fe3(CO)12,
affording high isolated yields and excellent ee’s which are
comparable with those obtained with the noble metal catalysts in
most cases.1−4 Under the conditions employed, there appears to
be no unambiguous correlation between the electron property
of substituents on the phenyl ring and the yield of products
(Table 2, entries 1, 5, and 8 vs 2, 14, and 19). However, the
enantioselectivities vary with the substitution position, with the
highest ee value being associated with, surprisingly somehow,
ortho-substituted ketones. For example, ee’s ranging from 97%
to 99% were obtained for ortho-substituted acetophenones
(Table 2, entries 4, 7, 13, 16), which are 2−7% higher than their
meta- and para-substituted analogues. In contrast, the precious
metal catalysts usually show the opposite trend and more
notably, none of them are known to afford ee’s higher than
1/Fe3(CO)12 for such ortho-substituted acetophenones. An
exception is found in the methoxy substituent in the AH with
1/Fe3(CO)12; the ketone gives decreasing ee values on going
from the para to meta and ortho substitution, a result which
could arise from hydrogen-bonding interactions between the
methoxy group and ligand NH proton (Table 2, entries 8−10).
Other acetophenones were also shown to be viable. For instance,
naphthyl and anthraceneyl ethanones were hydrogenated in
96−98% ee, and the bulky 1,1′-diphenylpropan-2-one gave rise
to 99% ee (Table 2, entry 26). There is no literature report on
the AH of this latter ketone, although ATH with Ir-PNNP
catalysts is known (94−99% ee).16e,f However, tetralone could
not be reduced efficiently with 1/Fe3(CO)12, affording only 25%
yield and 70% ee under the current conditions.
Still interestingly, excellent ee’s of 98−99% were observed
with α-substituted acetophenones, including those bearing the
ethyl, propyl, butyl, and sterically more demanding isopropyl
and cyclcohexyl groups (Table 3, entries 1−7). These results
highlight again the distinctive difference between 1/Fe3(CO)12
and the noble metal catalysts in AH of such problematic
ketones, with the iron catalyst displaying superior enantio-
selectivities in general. For instance, using the iron catalyst,
4-methyl propiophenone was reduced in 98% ee (Table 3,
entry 2), and the AH of both α-isopropyl- and α-cyclohexyl-
phenylmethanone gave 99% ee (Table 3, entries 5 and 7). In
comparison, the most-often used Ru-(diphosphine)(diamine)
catalysts are less enantioselective for these ketones (38−98%
ee).20,21 However, an iridium amido complex afforded >99%
ee,22 and in the case of 2,2,2-trifluoroacetophenone, the Noyori
Ru-(BINAP)(diamine) catalyst shows better performance than
1/Fe3(CO)12 (96% vs 92% ee).23
1
<1
none
<1
FeCl2·4H2O
Fe3(CO)12
>99
>99
<1
97
97
c
10
Fe3(CO)12
d
11
Fe3(CO)12
d
12
Fe3(CO)12
82
97
96
97
96
97
37
13
14
15
Fe3(CO)12
>99
78
Fe3(CO)12
Fe3(CO)12
20
e
16
Fe3(CO)12
26
f
17
Fe3(CO)12
3
a
Reaction conditions: acetophenone (1 mmol) with ketone/Fe/
(R,R,R,R)-1/base = 200:1:1:20 (molar ratio), MeOH (5 mL), initial
b
H2 pressure 50 bar, 45 °C and 12 h. Conversion and ee were
determined by GC analysis with a chiral CP-Chriasil-Dex CB column.
c
d
e
5 h reaction time with 20 mol % KOH. 5 h reaction time. AH at
f
25 °C. (R,R,R,R)-2 was used.
the macrocyclic ligand 1 with various iron compounds in
addition to Fe3(CO)12. To facilitate the screening, the catalyst
was generated in situ by reacting 1 with an iron species. As can
be seen from Table 1, while all the other iron complexes,
regardless of the oxidation state, failed to catalyze the AH in
question, the carbonyl cluster Fe3(CO)12 led to almost full
conversion in 12 h and a remarkable enantioselectivity of
97% ee (Table 1, entry 9), a value which is comparable to that
obtained with some of the most successful catalysts based
on the critical metals Ru, Os, Rh, and Ir.1−4 To the best of our
knowledge, this is the first example of highly efficient and
enantioselective AH of a ketone catalyzed by iron. A slightly
higher ee of 98% was obtained in the ATH of the same
substrate, and the ATH appears to be faster.15 The AH with the
1/Fe3(CO)12 combination involved reacting 1 (0.005 mmol)
with 1 equivalent of Fe3(CO)12 in methanol under 5 bar H2 at
45 °C for 1 h, before introducing 20 equiv of KOH and 1 mmol
of acetophenone; the resulting mixture was then stirred at
45 °C under 50 bar H2 for 12 h. It must be noted that the AH
becomes much slower and less enantioselective without the
initial 1 h pretreatment (vide infra). In addition, without H2,
no AH took place, showing that methanol is not acting as
the hydrogen source in the AH catalyzed by 1/Fe3(CO)12. The
base plays a critical role in the AH. In fact, when the
concentration of KOH was doubled, the AH was complete in
5 h (Table 1, entry 10). In its absence, little AH took place, and
lowering its concentration afforded a lower conversion. Similarly,
when a weaker base was used, a slower reaction resulted.
However, the enantioselectivity remained approximately the same
in all the scenarios (Table 1, entries 11−15) (For more details,
see the Supporting Information (SI)). These observations appear
AH of Heterocyclic Ketones. The 1/Fe3(CO)12 catalyst is
effective for the AH of heterocyclic ketones as well, furnishing
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a
Table 2. AH of Aromatic Ketones with 1/Fe3(CO)12
a
Reaction conditions: ketone (1 mmol) with ketone/Fe3(CO)12/(R,R,R,R)-1/KOH = 200:1:1:40 (molar ratio), initial H2 pressure 50 bar, 45 °C in
b
c
MeOH (5 mL). Isolated yield. Determined by GC or HPLC analysis. The absolute configuration was determined by comparison of the retention
times with the literature data (see the SI). (S,S,S,S)-1 was used.
d
good to excellent yields and ee’s (Table 4). Thus, 3- and
4-acetylpyridine were reduced to pyridinyl alcohols with 94%
and 90% ee, respectively (Table 4, entries 1 and 2). The lower
ee with 2-acetylpyridine may again be traced to possible inter-
actions of the pyridine nitrogen with the ligand NH functionality.
Acetylthiophenes are particularly suitable, as highlighted by
2,5-dimethyl-3-acetylthiophene which led to an ee of 99%
(Table 4, entries 4−8). In a previous study using a Ru(BICP)-
(diamine) (BICP = (2R,2R′)-bis(diphenylphosphino)-(1R,1R′)-
dicyclopentane) catalyst, the AH of 2-acetylthiophene and
5-Cl-2-acetylthiophene afforded 93% and 89% ee at −30 °C,
respectively.24 However, AH of acetylfurans and 2-acetylthiazole
produced only moderate ee values under the current conditions
(Table 4, entries 9, 10, and 13), reminiscent of the observa-
tions made with substrates bearing functionalities that could
hydrogen-bond with the NH proton of 1. In contrast, much
higher enantioselectivities were obtained for 3-acetylfuran and
5-acetylthiazole (Table 4, entries 11 and 14). The significantly
higher ee values observed for these two ketones indicate that
the ring heteroatom is more likely to interact with the ligand or
iron when it is next to the carbonyl group, possibly resulting in
hindering the face discrimination of the carbonyl group by the
catalyst at the step of hydride transfer.
AH of β-Ketoesters. To demonstrate further the utility of
the catalyst, we studied the AH of a class of functionalized
ketones, β-ketoesters. As shown in Table 5, excellent yields and
ee’s were again observed. In comparison with the ketones above,
a higher temperature and longer reaction time were necessary,
probably due to chelating interactions of the substrate with the
iron. However, hydrogen bonding interactions with the ligand
NH proton cannot be ruled out. Thus, the reduction of ethyl
3-oxo-3-phenylpropanoate afforded 95% yield with 97% ee in
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a
Table 3. AH of α-Substituted Aromatic Ketones with
1/Fe3(CO)12
Table 4. AH of Heterocyclic Ketones with 1/Fe3(CO)12
a
a
b
c
For reaction conditions, see Table 2. Isolated yield. Determined by
GC or HPLC analysis. The absolute configuration was determined by
comparison of the retention times with the literature data or analogy
d
e
(see the SI). (S,S,S,S)-1 was used. S/C ratio was 100/1.
30 h at 65 °C in ethanol (Table 5, entry 1). This result is
comparable with those from Ru-diphosphine catalysts (92−97%
ee).25 For these substrates, electron donating groups on the
phenyl ring appear to benefit both the reaction rate and
enantioselectivity, while electron withdrawing groups have the
opposite effect. This is seen by comparing the AH of methyl and
trimethoxy substituted keto esters (Table 5, entries 2, 5, and 7),
which completed in 22 h, with that of the halo substituted ones,
which necessitated more than 30 h for complete reduction and
showed slightly lower ee’s (Table 5, entries 3 and 4).
a
b
c
For reaction conditions, see Table 2. Isolated yield. Determined by
GC or HPLC analysis. The absolute configuration was determined by
comparison of the retention times with the literature data or analogy
(see the SI). (S,S,S,S)-1 was used. S/C ratio was 100/1.
d
e
Larger Scale AH. While most of the reactions above
were carried out at an S/C ratio of 200, lower catalyst loading
is possible. For instance, the AH of acetophenone with
1/Fe3(CO)12 proceeded smoothly at S/C = 500, being
complete in 10 h and affording 96% ee. At still a higher S/C
ratio of 1000, the ketone was hydrogenated in 84% conversion
and 92% ee in 24 h. Larger scale AH was also shown to be
feasible. Thus, AH of acetophenone (12.00 g) afforded the
desired chiral alcohol in 98% isolated yield (11.93 g) with
96% ee in 12 h (catalyst/KOH = 1:40), demonstrating the
commercial potential of this iron catalyst (eq 4).
as the active catalytic species. This assertion is supported by
several observations.
First, the reaction mixture is cloudy throughout the entire
AH process. Indeed, dynamic light scattering confirmed the
existence of iron particles when 1/Fe3(CO)12 in MeOH was
treated with H2 with or without KOH (For details, see the SI).
Second, as mentioned above, efficient AH necessitates reacting
1 with Fe3(CO)12 under 5 bar of H2 for 1 h before the AH
reaction (see Methods). Thus, when the AH of acetophenone
Mechanistic Observations. Preliminary studies suggest
that in contrast to AH with vast majority of the noble metal
catalysts, which is homogeneous in nature, the AH in question
appear to be heterogeneous, most likely involving iron particles
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a
cluster Fe3(CO)12), the AH of acetophenone proceeded to a
conversion of only 20% (S/C = 100). An even lower conversion
of 11% was observed when 0.3 equivalent of 1,10-phenanthro-
line was added (Table 6, entry 6). A similar effect was observed
with Hg(0), a poison commonly used to distinguish homo-
geneous catalysis from catalysis by metal particles.26 Thus,
1 equiv of Hg was sufficient to almost fully stop the AH
from occurring (Table 6, entry 9). Insightfully, a considerable
decrease in enantioselectivity was recorded in all three cases,
suggesting that the active catalytic species are changed by
the introduction of the poison molecules. For comparison, the
same AH reaction gave full conversion with 97% ee in 3 h in the
absence of the poison (Table 6, entry 1). These results indicate
that AH by 1/Fe3(CO)12 is probably heterogeneous, with
1-modified iron particles acting as the active catalyst. The
significant decrease in the catalytic activity and enantioselectivity
by a substiochiometric poison is consistent with adsorption of
the poison molecules onto, or amalgamation in the case of Hg
with,26 the surface of the particles, reducing the number of active
iron atoms that are expected to locate on the surface of the
particles and altering their interactions with 1. Although few
effective AH catalysts are known to be based on metal nano-
particles,28,29 Morris has recently shown that a Fe−N2P2
complex catalyzes transfer hydrogenation through the formation
of iron nanoparticles.27a
Table 5. AH of β-Ketoesters with 1/Fe3(CO)12
a
Reaction conditions: β-keto ester (1 mmol) with ester/Fe3(CO)12/
(R,R,R,R)-1/KOH = 50:1:1:40 (molar ratio), EtOH (5 mL), initial H2
pressure 50 bar, 65 °C and 30 h. Isolated yield. Determined by GC
or HPLC analysis. The absolute configuration was determined by
comparison of the retention times with the literature data (see the SI).
b
c
CONCLUSION
d
e
■
22 h reaction time. 35 h reaction time.
In summary, a remarkably effective iron catalyst has been
identified for the AH of ketones, showing enantioselectivities
approaching or even surpassing those achieved with the well-
established precious metal catalysts. The value of the catalyst is
further strengthened by its efficacy in related ATH reactions.15
A key element of the catalyst is the 22-membered macrocyclic
ligand 1, a feature that distinguishes the catalyst from almost all
known metal catalysts successful in AH and ATH reactions.
While how the ligand induces asymmetry and what active iron
species are involved in the AH concerned remain to be
delineated in detail, the macrocyclic feature of the ligand points
to a new direction in developing viable iron catalysts for
asymmetric reduction and probably for other reaction as well.
was carried out under the conditions of Table 2 except without
the initial 1 h pretreatment, a lower conversion of 72% and
a lower ee of 83% were obtained in 15 h reaction time. This
observation suggests that efficient AH with 1/Fe3(CO)12 involves
a period in which active and selective catalytically species is
generated under H2, a phenomenon bearing resemblance to
hydrogenation by heterogeneous catalysts, where catalytically
active metal particles are often formed through an induction
period.26,27
Third, a significant poisoning effect was observed when
poisons of diverse nature26 were introduced separately to the
AH by 1/Fe3(CO)12 (Table 6). Thus, in the presence of sub-
stiochiometric PPh3 (0.3 equivalent, relative to the iron carbonyl
ASSOCIATED CONTENT
* Supporting Information
■
S
Table 6. Effect of Poisoning Additives on the AH of
Further details of the AH reactions, including characterization
data of products, GC/HPLC trace records, and technical
details. This material is available free of charge via the Internet
at http://pubs.acs.org.
a
Acetophenone with 1/Fe3(CO)12
AUTHOR INFORMATION
Corresponding Authors
jxiao@liv.ac.uk
■
b
c
c
]
]
]
Entry
Additives
Quantity[ Time [h] Conv (%)[ Ee (%)[
1
2
3
4
5
6
7
8
9
none
PPh3
PPh3
PPh3
3
10
10
10
10
10
10
10
10
>99
8
97
56
84
92
1
jxgao@xmu.edu.cn
0.3
0.1
1
20
98
<1
11
92
<1
4
Author Contributions
§Y.L. and S.Y. contributed equally.
1,10-phenanthroline
1,10-phenanthroline
1,10-phenanthroline
mercury
Notes
0.3
0.1
3
75
83
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
mercury
1
45
■
a
This work was supported by the National Natural Science
Foundation of China (No. 21173176), the Program for
Changjiang Scholars and Innovative Research Team in
University (No. IRT1036), and the University of Liverpool.
Reaction conditions: ketone (1 mmol), with ketone/Fe3(CO)12/
(R,R,R,R)-1/KOH = 100:1:1:40 (molar ratio), 50 bar H2, 45 °C in
MeOH. Equivalent, relative to Fe3(CO)12. Conversion and ee were
determined by GC analysis with a chiral CP-Chriasil-Dex CB column.
b
c
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Article
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Y.L. is grateful to China Scholarship Council for a State
Scholarship. We also thank Prof. Steve Rannard and Dr. Fiona
Hatton for assistance in the DLS experiments.
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