Cooperative catalysis: Combining an achiral metal catalyst with a chiral Br?nsted acid enables highly enantioselective hydrogenation of imines

Article abstract of DOI:10.1002/chem.201302437

Asymmetric hydrogenation of imines leads directly to chiral amines, one of the most important structural units in chemical products, from pharmaceuticals to materials. However, highly effective catalysts are rare. This article reveals that combining an ac

Full text of DOI:10.1002/chem.201302437

FULL PAPER
DOI: 10.1002/chem.201302437
Cooperative Catalysis: Combining an Achiral Metal Catalyst with a Chiral
Brønsted Acid Enables Highly Enantioselective Hydrogenation of Imines
Weijun Tang, Steven Johnston, Chaoqun Li, Jonathan A. Iggo, John Bacsa, and
Jianliang Xiao*[a]
Abstract: Asymmetric hydrogenation
of imines leads directly to chiral
amines, one of the most important
structural units in chemical products,
from pharmaceuticals to materials.
However, highly effective catalysts are
rare. This article reveals that combin-
ing an achiral pentamethylcyclopenta-
dienyl (Cp*)–iridium complex with a
chiral phosphoric acid affords a catalyst
that allows for highly enantioselective
hydrogenation of imines derived from
aryl ketones, as well as those derived
from aliphatic ones, with ee values
varying from 81 to 98%. A range of
achiral iridium complexes containing
diamine ligands were examined, for
which the ligands were shown to have
a profound effect on the reaction rate,
enantioselectivity and catalyst deactiva-
tion. The chiral phosphoric acid is no
less important, inducing enantioselec-
tion in the hydrogenation. The induc-
tion occurs, however, at the expense of
the reaction rate.
Keywords: asymmetric hydrogena-
tion · Brønsted acid · cooperative
catalysis · imines · iridium
Introduction
the chiral complex B with the chiral phosphoric acid HA,
activates H2 and catalyses the asymmetric hydrogenation of
acyclic imines[9a] and the reductive amination of ketones[9b–c]
with excellent enantioselectivities (Scheme 1). The reduction
was thought to proceed through an ionic pathway involving
metal–organo cooperative catalysis,[11] in which the phos-
phate anion pairs with the iminium cation,[12] thereby influ-
encing the face-selective addition of hydride D to the imino
C=N bond and thus influencing the enantioselectivity. In
line with this hypothesis, dramatic changes in enantioselec-
tivity and reversal of amine configuration were observed on
altering the steric bulk of (R)-HA, or on replacing the (S,S)-
diamine with an (R,R)-diamine ligand in B.[9a] These results
Over the past few decades, a great deal of effort has been
focussed on the asymmetric reduction of imines to access
optically active amines,[1–5] ubiquitous functionalities in fine
chemical, agrochemical and pharmaceutical products.[6]
Among the approaches reported so far, asymmetric hydro-
genation with cheap, clean hydrogen gas offers a totally
atom-economical and very convenient route. However, in
contrast to the great success in asymmetric hydrogenation of
prochiral olefins and ketones,[7] the highly enantioselective
hydrogenation of imines is still challenging. In particular,
apart from isolated examples,[8,9] few catalysts are known
that can deliver enantioselectivity higher than 80% ee in
the hydrogenation of imines derived from aliphatic
ketones.[2a,c,f,g,k] Herein, we report that by exploiting achiral–
chiral metal–organo cooperative catalysis, acyclic imines, in-
cluding aliphatic ones, can be readily hydrogenated with
enantioselectivities of up to 98% ee.
The combination of metal catalysts with organocatalysts
has recently become one of the most active and exciting
topics in catalysis, allowing reactivity and selectivity patterns
that are inaccessible within the fields of either homogeneous
or organo-catalysis alone.[10] We reported in 2008 that the
chiral [Cp*IrACHTUNGTRENNUNG(diamine)] (Cp*=pentamethylcyclopentadien-
yl) complex [B+][AÀ], generated from the protonation of
[a] Dr. W. Tang, S. Johnston, Dr. C. Li, Dr. J. A. Iggo, Dr. J. Bacsa,
Prof. J. Xiao
Liverpool Centre for Materials & Catalysis
Department of Chemistry, University of Liverpool
Liverpool, L69 7ZD (UK)
E-mail: jxiao@liv.ac.uk
Scheme 1. Hydrogenation of imines with a cooperative catalytic system
resulting from B and HA (Ar=2,4,6-triisopropylphenyl; PMP=para-me-
thoxyphenyl).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302437.
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suggested to us that it might be possible to combine a chiral
HA with an achiral analogue of B to effect the same asym-
metric hydrogenation, with the former inducing chirality at
the latter.[13–15] This was not very far-fetched, since chiral
phosphoric acids had been demonstrated to be able to direct
highly enantioselective hydride transfer from achiral
organo-hydride donors to imines.[4,16] In fact, while our
search for the optimal chiral–achiral “couple” was in prog-
ress,[14] Rueping and co-workers reported, in 2011, that
chiral N-trifylphosphoramide can induce chirality at an achi-
ral analogue of B, although the enantioselectivity was low
(32% ee) in the hydrogenation of quinoline.[17] More recent-
ly, Beller and co-workers developed a highly effective cata-
lytic system that combines an achiral iron complex with a
chiral phosphoric acid,[2c] affording excellent ee values (up
to 97%) for aryl ketone-derived imines, but lower values
(up to 83%) for the analogous aliphatic imines.
Described below are our results on the asymmetric hydro-
genation of acyclic imines obtained by using an easily acces-
sible achiral [Cp*IrACHTUNGTRENNUNG(diamine)] catalyst coupled with a chiral
phosphoric acid. The use of a chiral organocatalyst to
induce chirality at an achiral metal complex, or vice versa, is
interesting, not only because of “economy” in chirality but
also because it gives an increased number of potential cata-
lysts. In a very recent communication built on the study of a
model hydrogenation, we provided detailed mechanistic in-
sight into how the chiral acid and achiral metal catalyst act
cooperatively to effect the highly enantioselective hydroge-
nation.[13]
Scheme 2. Achiral metal catalysts synthesised and studied for cooperative
hydrogenation (Ar=2,4,6-triisopropylphenyl; Ts=para-toluenesulfonyl).
(Scheme 1), the conversion and enantioselectivity were both
decreased considerably when using the achiral complex C1
in the presence of HA (Table 1, entry 1). Replacing the hy-
drogen atom with an ethyl group on the nitrogen atom in C1
did not lead to a better catalyst (C2; Table 1, entry 2). Some-
Results and Discussion
Table 1. Screening of achiral metal catalysts for the asymmetric hydroge-
Identification of catalysts: Following on from our initial
search for a viable chiral–achiral combination catalyst,[14] we
synthesised a series of neutral 16eÀ complexes, exemplified
by C1–C11, from cheaply available ethylene diamine and its
derivatives (Scheme 2).[18] Mixing the phosphoric acid HA
with C leads to its protonation at the amido nitrogen atom,
forming an analogue of B+, that is, the active catalyst [C+]
[AÀ] [Eq. (1)].[9,13,19]
nation of imine 1a.[a]
Entry
C
HA
[%]
t
Conv.
[%][b]
ee
[h]
[%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14[d]
15[e]
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C4
C4
C4
C4
2
2
2
2
2
2
2
2
2
2
2
1
1
1
1
5
5
5
5
5
5
5
5
5
5
5
5
12
12
12
10
15
2
100
100
100
100
100
90
50
11
82
100
87
50
48
–
97
94
95
83
97
94
93
–
97
97
98
97
With these complexes in hand, the asymmetric hydrogena-
tion of a model imine, 1a, was examined under the same
conditions as reported previously, that is, 20 bar of H2 in a
non-polar solvent, toluene, at room temperature, with the
catalyst [C+][AÀ] formed in situ by combining C with
HA.[9a] The results are shown in Table 1. Compared with
those obtained with the chiral combination [B+][AÀ]
43
[a] The reaction was carried out with 1a (0.15 mmol) in toluene (0.7 mL).
[b] The conversion was determined by 1H NMR spectroscopy. [c] Deter-
mined by HPLC analysis; configuration was assigned by comparison with
the literature (see the Supporting Information). [d] The temperature was
108C. [e] 5 bar of H2 was used.
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Cooperative Catalysis
FULL PAPER
what surprisingly, when a cyclohexylmethyl group was instal-
led (C3), little hydrogenation was observed (Table 1,
entry 3), highlighting the critical effect of the diamine struc-
ture on the catalysis.[20] A further search led to the discovery
of C4, in which the NH hydrogen is replaced with a benzyl
group, and when C4 was combined with HA, an excellent
enantioselectivity of 97% ee was observed along with com-
plete conversion of 1a (Table 1, entry 4).
Aiming to further improve the enantioselectivity, C4 was
altered and the resulting complexes were tested. Although
none of the complexes (C5–C11) gave better results when
combined with HA, we made some interesting observations.
Introducing an electron-withdrawing group on either the
benzyl or sulfonyl unit resulted in a lower ee (Table 1, com-
pare entries 4, 5 and 8 with 7 and 10), and in the case of the
latter, the reaction was significantly slower (Table 1, com-
pare entry 6 with 10 and 11). The bulky Ar group in C4 is
beneficial; replacing it with para-tolyl (C6) led to a slight de-
crease in the ee (Table 1, entry 4 vs. 6), but increasing the
bulk of the benzyl unit has an adverse effect on both the ee
and reaction rate (Table 1, entry 6 vs. 9). The effect of these
substituents on the hydrogenation may originate from their
effect on the ternary transition state in the hydride-transfer
step.[13]
ed N-aryl ketimine could be reduced with high enantioselec-
tivity (Table 2, entry 16).
For most of the reactions in Table 2, the enantioselectivi-
ties obtained with the achiral–chiral couple C4–HA are com-
parable to those from the reaction in the presence of the
chiral–chiral B–HA catalyst.[9a] However, C4–HA led to sig-
nificantly higher ee values in the case of the -CN- and -NO2-
substituted imines 1h, 1i and 1l. For example, for 1l,
92% ee was observed with C4–HA (Table 2, entry 12) in
comparison with 84% ee with B–HA.[9a] Why this is the case
is not immediately clear to us.
Asymmetric hydrogenation of aliphatic ketone-derived
imines: In contrast to aromatic imines, successful examples
of asymmetric hydrogenation of imines derived from ali-
phatic ketones are rare.[2a,c,f,g] Subsequent to the study above,
we explored the use of the same catalytic system for asym-
metric hydrogenation of the more challenging aliphatic
N-aryl imines. We started our investigation by using 4-me-
thoxy-N-(4-methylpentan-2-ylidene)aniline as a model sub-
strate (Scheme 3, R=p-OMe), which afforded a high enan-
With C4, the loading of the phosphoric acid HA can be re-
duced without compromising the ee value but the hydroge-
nation became slower (Table 1, entry 12). Full conversion
was, however, reached after a longer reaction time (12 h;
Table 1, entry 13). As may be expected, a lower temperature
improved the enantioselectivity slightly but reduced the re-
action rate (Table 1, entry 14). Additionally, the pressure of
hydrogen impacts the hydrogenation rate, with lower pres-
sures leading to lower conversion (Table 1, entry 15).
Scheme 3. Effect of substrate size on enantioselectivity.
tioselectivity of 92% ee under the catalysis by a chiral–
chiral couple analogous to B–HA.[9a] However, combining
the achiral catalyst C4 with HA resulted in a much lower
enantioselectivity of 43% ee. A moderate increase in ee was
observed when C4 was replaced with C5. Since increasing
the steric bulk of imines may render their C=N faces easier
to discriminate,[2a,g] we went on to study the hydrogenation
of imines with different substitution patterns. As can be
seen from Scheme 3, the enantioselectivity increased pro-
gressively as the imine became sterically more demanding,
that is, as the substitution position at the N-aryl ring
changed from para to meta to ortho, reaching a remarkable
value of 89% ee. This observation may not be surprising,
considering that the interaction between the phosphate AÀ
and the iminium cation is non-covalent and weak; therefore,
the enantioselectivity is expected to be sensitive to the steric
bulk of the imine.[12,13]
To probe the generality of the C5–HA combination for
aliphatic ketone-derived imines, a series of ortho-substituted
N-aryl aliphatic imines were subjected to the hydrogenation.
As can be seen from Table 3, all of the substrates examined
were hydrogenated in high yields and enantioselectivities. In
general, higher enantioselectivities were observed for imines
with bulkier ortho-substituents on the phenyl ring. For in-
Asymmetric hydrogenation of acyclic aromatic imines:
Having established a highly enantioselective achiral–chiral
combination of catalysts for the hydrogenation of imine 1a,
we turned our attention to examining the scope of the C4–
HA-couple-catalysed asymmetric hydrogenation of substi-
tuted acyclic aromatic imines 1b–p. The results are shown in
Table 2. In general, all substrates examined were reduced
smoothly in excellent enantioselectivities and yields, with ee
values ranging from 92 to 98%. Notably, this catalytic
system tolerates not only functional groups with diverse
electronic properties, for example, -MeO, -CN, -Br and
-NO2, but also substituents at different positions (Table 2,
entries 2–4). Imine substrates bearing ortho-substituents on
the phenyl ring necessitated harsher conditions for the reac-
tion to proceed with a reasonable rate; however, the enan-
tioselectivity remained high (Table 2, entries 2, 4 and 11).
The low reactivity of these imines likely stems from the
ortho-substitution, which increases the steric bulk of the
imine, impeding its approach to the Ir H hydride.[13] Replac-
À
ing the anisidine in 1 with other aryl groups, such as aniline
or para-bromoaniline, does not appear to impact the hydro-
genation, with excellent enantioselectivities and high yields
again observed (Table 2, entries 14–15). Finally, a-substitut-
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J. Xiao et al.
Table 2. Asymmetric hydrogenation of acyclic aromatic imines.[a]
Entry
1
Sub.
Product
Yield
[%][b]
ee
Entry
9
Sub.
Product
Yield
ee
[%][c]
[%][b]
[%][c]
1a
95
94
97
97
1i
93
96
98
2
1b
10
1j
92
3
1c
1d
1e
1 f
95
93
93
97
98
97
98
97
11[d,e]
1k
1l
93
93
95
96
94
92
98
98
4[d,e]
12
5
13
1m
1n
6
14
7
8
1g
1h
92
95
98
96
15
1o
1p
95
93
97
92
16[d]
[a] All reactions were carried out with the substrate (0.15 mmol), toluene (0.7 mL), and H2 (20 bar), at 208C for 12 h. [b] Yields of the isolated product.
[c] The enantioselectivities were determined by HPLC; S configuration, assigned by comparison with the literature (see the Supporting Information).
[d] The reactions were carried out in 20 h with 2% of the phosphoric acid HA. [e] The pressure was 30 bar.
stance, the ethyl-substituted imines always afford higher ee
values than their methyl analogues (Table 3, entries 4, 8, 11,
14 and 17 vs. 2, 7, 10, 13 and 16.).
their preparation or method of use can impact the catalytic
activity. We noted that when C4 or C5 was mixed with HA in
the absence of 1a or was not used immediately upon
mixing, the resulting species [C+][AÀ] was much less effec-
tive in catalysing the hydrogenation. Further study showed
that under such conditions, the benzyl group in the cation
undergoes cyclometallation with the iridium atom, forming
a catalytically inactive complex. This was verified by X-ray
diffraction analysis in the case of C6, which formed a yellow
precipitate when protonated with HA in toluene at ambient
temperature (Scheme 4). The X-ray analysis revealed the
formation of a stable cyclometallated complex C12. This
complex does not catalyse the hydrogenation of 1a. Howev-
er, its formation is suppressed in the presence of an imine,
presumably due to coordination of the imine to the cationic
16eÀ iridium centre. Thus, in the absence of a coordinating
substrate, [C+][AÀ] deactivates through cyclometallation.
It is worth noting that the catalytic system tolerates the
presence of reducible C=C double bonds, affording excellent
enantioselectivities for imines 3i–k. More remarkably, this
C5–HA catalyst is capable of discriminating, highly effective-
ly, an ethyl group from a butyl group (Table 3, entries 12–
14) or from a propyl (Table 3, entries 15–17) group, giving
ee values of up to 94%. To the best of our knowledge, these
ee values represent some of the highest enantioselectivities
ever reported for aliphatic N-aryl imines. Only a few scat-
tered examples are known for which higher ee values have
been observed.[2g,8]
Catalyst deactivation: Although the catalysts C4–HA and
C5–HA are highly effective for the reaction in question,
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Cooperative Catalysis
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Table 3. Asymmetric hydrogenation of aliphatic ketone derived imines with C5–HA.[a]
Entry
Sub.
3a
Product
Yield
[%][b]
ee
Entry
10
Sub.
3j
Product
Yield
[%][b]
ee
[%][c]
[%][c]
1
2
93
91
89
94
95
95
89
92
3b
11
3k
3
4
3c
3d
93
95
94
97
12
13
3l
94
95
85
94
3m
5
6
3e
3 f
96
94
94
84
14
3n
95
94
15
16
17
3o
3p
3q
93
94
90
81
89
91
7
8
9
3g
3h
3i
93
95
96
85
91
92
[a] All reactions were carried out with the substrate (0.15 mmol), toluene (0.7 mL), and H2 (20 bar), at 208C for 12 h. [b] Yields of the isolated product.
[c] Enantioselectivities determined by HPLC, with configuration assigned by analogy with the literature (see the Supporting Information).
The pros and cons of the chiral acid: The cooperative asym-
metric hydrogenation by C–HA proceeds via a ternary com-
plex comprised of an iridium hydride, an iminium ion and
[AÀ], mainly bound together through hydrogen bonding.[13]
Although the phosphate is highly effective in chirality relay,
its bulk retards the hydride transfer and hence reduces the
reaction rate. This can be clearly seen in the comparison
shown in Scheme 5, in which the hydrogenation was com-
plete in 12 h with the catalyst generated from C6 and HA
but a mere 11 min was required with the catalyst derived
from the complex F and NaBARF (BARF=tetrakis
ACHTUNGTRENNUNG[3,5-
bis(trifluoromethyl)phenyl]borate). The non-hydrogen-
bonding BARF anion means that the hydride transfer from
the iridium to the “naked” iminium ion (Scheme 1) is much
faster, but proceeds with no enantioselectivity.
Scheme 4. Formation of a catalytically inactive cyclometallated complex
from protonated C6. For the structural details of C12, see the Supporting
Information.
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J. Xiao et al.
Conclusion
We have developed a new cooperative metal–organo cata-
lytic system, in which a chiral Brønsted acid induces chirali-
ty in an achiral-metal-catalysed hydrogenation reaction. The
catalyst is highly efficient, affording excellent enantioselec-
tivities and high yields in the hydrogenation of imines de-
rived from either aryl or aliphatic ketones, thus opening a
new avenue for accessing chiral amines. However, the enan-
tioselectivity is attained at the expense of the reaction rate,
due to the steric hindrance created by the chiral acid.
Scheme 5. Comparison of the hydrogenation of 1a with a catalyst derived
from F and NaBARF and one derived from C6 and HA.
Experimental Section
We have followed these reactions by use of in situ
1H high-pressure (HP) NMR spectroscopy at a constant H2
pressure of 20 bar at 258C. Figure 1 gives the conversion–
A mixture of the imine (0.15 mmol) and phosphoric acid HA (1 mol%)
in toluene (0.5 mL) was stirred at room temperature for 5 min. There-
after, a solution of C4 or C5 (1 mol%)
in toluene (0.2 mL) was added and
the mixture was transferred to
a
stainless steel autoclave. The hydro-
genation was performed under H2
(20 bar) whilst the mixture was stir-
red at 208C for 12 h. After carefully
releasing the hydrogen gas in a fume
hood, the solvent was removed and
HCl (1m, 1 mL) was added. After
stirring for 10 min, saturated aqueous
sodium bicarbonate was added slowly
and the mixture was extracted with
ethyl acetate (3ꢁ1 mL). The com-
bined solution of ethyl acetate was
dried with Na2SO4 and the solvent
was removed. The residue was puri-
fied by passing it through a silica gel
column eluted with hexane/CH2Cl2
(1:1–0:1) to give the pure amine
product. The enantiomeric excess was
determined by HPLC on a chromato-
graph equipped with a chiral column
(OB-H or OD-H). The configuration
of amines 2a–2p was determined to
be S by comparison of their HPLC
&
Figure 1. Time profiles for the hydrogenation of 1a with catalysts derived from F and NaBARF ( ) and C6 and
HA ( ) monitored by in situ 1H HP NMR spectroscopy. Reactions were carried out with 0.09 mmol substrate
^
in [D8]toluene (0.5 mL), at 20 bar H2 pressure and 258C.
time profiles obtained for these reactions. Examination of
behaviour with that of authentic samples.[16b] For amines 4a–4q, the con-
figuration was assumed to be S by analogy with the reported literature.[9]
the profiles reveals that the initial rate of the hydrogenation
with F–NaBARF is 22 times faster than that with C6–HA.
More interestingly, the former proceeds at an approximately
constant rate whereas the latter becomes much slower after
the first few hours (see the Supporting Information for more
details), suggesting that the counteranion alters the reaction
mechanism. The linear dependence of the conversion on
time in the case of F–NaBARF is consistent with fast, non-
turnover-limiting hydride transfer to the iminium ion over
the entire course of the reaction (Scheme 1), whereas with
C6–HA the catalytic turnover is likely to be controlled by
the hydride transfer to the iminium ion. The rate of the
former is most likely limited by the hydride-formation step.
These observations, together with those mentioned previous-
ly,[13] support the view that the increased bulk of the chiral
acid inhibits the reduction of the imine and yet, paradoxical-
ly, the reduction occurs enantioselectively only as a result of
the phosphate intervention by hydrogen bonding with both
the metal catalyst and the substrate.
Acknowledgements
The authors thank the EPRSC for funding support on grant EP/G031444
(W.J. Tang and S. Johnston). Mass spectrometry data was acquired at the
EPSRC UK National Mass Spectrometry Facility at Swansea University.
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1760; for a significant industrial application, see: c) H.-U. Blaser,
Adv. Synth. Catal. 2002, 344, 17–31.
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ˇ ´
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Cooperative Catalysis
FULL PAPER
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Received: August 13, 2013
Published online: September 9, 2013
Chem. Eur. J. 2013, 19, 14187 – 14193
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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