Primary amine-metal Lewis acid bifunctional catalysts based on a simple bidentate ligand: Direct asymmetric aldol reaction

Article abstract of DOI:10.1039/c0cc00917b

A novel class of primary amine-metal Lewis acid bifunctional catalysts based on a bidentate ligand was developed. These catalysts were highly efficient in catalyzing the direct asymmetric aldol reactions of ketones offering excellent stereoselectivity. Th

Full text of DOI:10.1039/c0cc00917b

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Primary amine-metal Lewis acid bifunctional catalysts based on a simple
bidentate ligand: direct asymmetric aldol reactionwz
Philias Daka, Zhenghu Xu, Alexandru Alexa and Hong Wang*
Received 13th April 2010, Accepted 1st June 2010
DOI: 10.1039/c0cc00917b
A novel class of primary amine-metal Lewis acid bifunctional
catalysts based on a bidentate ligand was developed. These
catalysts were highly efficient in catalyzing the direct
asymmetric aldol reactions of ketones offering excellent stereo-
selectivity. The aldol reactions required a low catalyst loading
(2.5 mol%), and were water compatible.
The combination of organocatalysis with transition metal
catalysis has recently emerged as a promising strategy to
discover new carbon-carbon and carbon-heteroatom forming
Fig.
1
Structure of ligands and illustration of the
reactions.1 Given the unique activation modes of organo-
catalysis and the well-established rich chemistry of metal
catalysis, the combination of these two areas holds great
potential to achieve organic transformations that are not
possible through organocatalysis or metal catalysis alone.
Enamine-based catalysis plays a crucial role in organocatalysis.2
In recent years, several publications combining secondary
amine-based enamine catalysis with transition metal catalysis
have shown unprecedented organic transformations,1,3
demonstrating the power of the combined systems. The
major challenge in developing Lewis base-metal Lewis acid
bifunctional catalytic systems lies in the acid–base quenching
reaction (by coordination) leading to catalyst inactivation.4a
The general approach to solving this problem is to use a soft
metal Lewis acid along with a hard Lewis base, or vice-versa,
followed by fine tuning the reaction condition until the desired
product is formed as the major product.3,4 We intend to take a
different approach. In our system, the Lewis base (L-amino
acids) is tethered to a chelating ligand, which serves as a
‘‘trap’’ for the incoming metal. In this way, the base and the
metal Lewis acid are brought to close proximity without
interacting with each other (Fig. 1). A unique advantage of
this system is that the Lewis acidity can be easily tuned by
simply replacing it with a different metal, and the ‘‘softness’’ of
the metal does not need to be considered for the purpose of
preventing the acid–base interaction.
bifunctional catalyst
Compared to a majority of those primary amine-based organo-
catalysts,6 the activity and diastereoselectivity of these catalysts
were significantly enhanced for the asymmetric direct aldol
reactions. In our continuous effort to develop enamine-metal
Lewis acid multi/bifunctional catalysts, we feel that it is necessary
to enrich our ligand repository in order to fully utilize this
new concept, and more importantly, to open it up to wider
exploitation. In this work, we wish to introduce another novel
class of primary amine-metal Lewis acid bifunctional catalysts
based on a simple bidentate ligand, and their successful
application to the asymmetric direct aldol reactions of ketones.
Seven bidentate ligands tethered with chiral primary amines
were prepared (Fig. 1). The synthesis of these ligands was
achieved through coupling reactions between N-Boc protected
L-a amino acids and 2-aminopyridine followed by deprotection
(see details in Supporting Information). We expect that the
metal will serve as a Lewis acid activating the aldol acceptor,
and the primary amine will serve as a Lewis base to form an
enamine intermediate with the aldol donor (Fig. 2).
We started investigating the catalytic activities of these
ligands with the aldol reaction of cyclohexanone with
4-nitrobenzaldehyde in neat conditions (Table 1). We first chose
Cu(SbF6)2 as the Lewis acid, as it was the best match for our
tridentate system.5 In order to understand how coordination
affects the activities of these catalysts, two different ligand/metal
ratios (1/1 and 2/1) (entries 1–6) were used. It turned out that 2/1
ligand/metal ratio gave much higher activity and higher stereo-
selectivity. The ligand/metal ratio of 2/1 was then selected to
examine the rest of the ligands. While all ligands displayed very
high activity in terms of yield and reaction time, 1a and lg
showed exceptionally high activity completing the reaction in
only three hours, much faster than the reactions catalyzed by
most primary amine based organocatalysts which in general
require 2 to 3 days for the completion.6 These bidentate ligand
systems are also much more active than our tridentate ligand
systems.5 The much higher activity may be attributed to
the coexistence of the two primary amines in the symmetric
Despite the potentials of multi/bifunctional catalysts, the
development of these systems is a formidable task due to the
simultaneous requirements for the distance, rigidity, orientation
and interactions of these functional groups. In previous work, we
showed the first example of primary amine-metal Lewis acid
bifunctional catalysts using a chelating tridentate ligand.5a
Department of Chemistry and Biochemistry, Miami University,
Oxford, OH 45056, US. E-mail: wangh3@muohio.edu;
Fax: 01 (513)529-5715; Tel: 01(513)529-2824
w This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
z Electronic supplementary information (ESI) available: Detailed
experimental procedures, characterization data for all new
compounds, and HPLC data. See DOI: 10.1039/c0cc00917b
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Table 2 Aldehyde scopea
Entry R1
L
Product Yield(%)b Anti/sync Ee(%)d
Fig. 2 Proposed transition state
Table 1 Ligand screeninga
1
2
3
4
5
6
7
8
4-NO2C6H4
1a 3a
1g
1a 3b
1g
1a 3c
1g
1a 3d
1g
80
90
86
80
84
88
83
85
86
89
94
90
70
84
75
83
70
70
25/1
9/1
17/1
3/1
30/1
4/1
16/1
3/1
14/1
4/1
12/1
3/1
12/1
7/1
10/1
4/1
98
499
96
499
95
499
97
499
499
499
97
499
94
97
83
89
3-NO2C6H4
2-NO2C6H4
4-CNC6H4
2,6-Cl2C6H3
9
1a 3e
1g
4-COOMeC6H4 1a 3f
Entry Ligand T (h) L:M Yield (%)b Anti/Sync Ee (%)d
10
11
12
13
14
15
16
17
18
1g
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1d
1e
1f
24
3
1 : 1
2 : 1
1 : 1
2 : 1
1 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
78
80
81
86
82
90
84
92
64
90
65
14/1
25/1
10/1
16/1
6/1
16/1
20/1
9/1
96
98
93
94
76
80
90
90
84
499
79
4-BrC6H4
4-ClC6H4
C6H5
1a 3g
1a 3h
1a 3i
1g
1a 3j
1a 3k
24
10
24
10
10
10
10
3
2-Naphthyl
4-MeC6H4
8/1
5/1
92
82
a
The reactions were performed with 0.2 mmol of aldehyde at room
b
temperature in 1 mL of cyclohexanone for 3-48 h. Combined yield.
9
10
11
7/1
9/1
3/1
1g
2
c
d
Determined by 1H NMR. Determined by chiral HPLC.
34
a
The reactions were performed with 0.2 mmol of 4-nitrobenzaldehyde
b
and 1 mL of cyclohexanone at room temperature (neat). Combined
Table 3 Catalyst loadinga
c
yield. Determined by H NMR. Determined by chiral HPLC.
1
d
2/1 ligand/metal system. 1a and lg also provided the best
diastereoselectivity (25/1, dr) and enantioselectivity (499%, ee)
(entries 2 and 10), respectively. For comparison, L-proline
tethered ligand 2 was prepared. The secondary amine based
ligand 2 resulted in much lower activity and stereoselectivity
(entry, 11), another example of primary amines showing superior
enamine catalytic activity than secondary amines.
Cat.
Entry (mol%) (h)
Time
Conversion(%) Yield(%)b Anti/Sync Ee(%)d
1
2
3
4
5
6
7
20
15
10
5
2.5
1.0
0.5
3
4
6
10
30
100
100
100
100
100
80
84
80
85
80
67
40
25/1
16/1
16/1
16/1
11/1
9/1
98
98
98
98
96
93
89
Metal and solvent screenings were carried out next using
ligand 1a in neat conditions (see Supporting Information). CuII
salts offered superior activities and stereoselectivities than other
metals including CoII, ZnII, YbIII, and NiII; counter anion also
played a role in determining the stereoselectivity as Cu(SbF6)2
displayed much better diastereoselectivity and enantioselectivity
than Cu(OTf)2. A range of solvents including DMSO, THF,
CH3CN, toluene, MeOH, DCM, and DMF were examined in
the presence of Cu(SbF6)2. The best results were obtained
from the neat conditions (see Supporting Information).
The substrate scope of the aldol reactions of cyclohexanone
was then investigated using ligand 1a and 1g under optimized
conditions (Cu(SbF6)2/neat, Table 2). Very good to excellent
diastereoselectivity (up to 30/1) and enantioselectivity (up to
499% ee) were achieved with all the electron-poor aromatic
aldehydes (entries, 1–14) for both ligands; while 1g gave
excellent enantioselectivity (499% ee, entries 2, 4, 6, 8, 9, 10
and 12), their diastereoselectivity was lower than those of 1a.
Electron-rich aromatic aldehydes also furnished with good
diastereoselectivities and enantioselectivities (entries, 15–18);
the aldol reaction of acetone with 4-nitrobenzaldehyde
resulted in 81% ee (see Supporting Information).
144 95
144 50
4/1
a
The reactions were performed with 0.2 mmol of aldehyde and 1mL
b
cyclohexanone at room temperature. Combined yield. Determined
1
by H NMR. Determined by chiral HPLC.
c
d
The effect of catalyst loading on the aldol reaction
of cyclohexanone with 4-nitrobenzaldehyde using ligand
1a/Cu(SbF6)2 was examined (Table 3). Although an overall
decreasing trend in activity and stereoselectivity was observed
when less catalyst was used, the stereoselectivity did not show
much difference with a catalyst loading between 5 to 20 mol%
(B98% ee, 16/1–25/1 dr, entries, 1–4), and the catalyst
remained very active in terms of both yield and reaction time
with a loading as low as 2.5 mol% (entry, 5).
The performance of the catalytic system (1a/Cu(SbF6)2) was
also examined in the presence of water using the aldol
reactions of cyclohexanone with a number of aromatic aldehydes
(Table 4). These aldol reactions were water tolerant
(H2O/cyclohexanone, v/v, 1 : 1 to 3 : 1), however, with slight
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Table 4 Reaction in watera
Entry
R1
H2O/Cyclohexanoneb
Product
Yield(%)c
Anti/Synd
Ee(%)e
1
2
3
4
5
6
7
8
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-CNC6H4
4-ClC6H4
4-BrC6H4
4-CO2MeC6H4
2-Naphyl
1/1
2/1
3/1
2/1
2/1
2/1
2/1
2/1
3a
3a
3a
3d
3h
3g
3f
62
65
66
65
57
53
70
45
11/1
10/1
9/1
6/1
7/1
6/1
5/1
8/1
96
95
93
93
92
89
94
90
3j
a
b
c
The reactions were performed with 0.2 mmol of aldehyde. Volume ratio, total volume: 1 mL. Combined yield. Determined by
d
1H NMR. Determined by chiral HPLC.
e
decreases in both activity and stereoselectivity. The decreasing
trend became slightly more severe when more water was
included in the reaction system (entries, 1–3).
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¨
The cooperative nature of this catalytic system was revealed by
the fact that Cu(SbF6)2 or the ligand (1a) alone could
not catalyze the aldol reaction of cyclohexanone with
4-nitrobenzaldehyde. All the aldol reactions of cyclohexanone
predominately generated the anti aldol products with (2S, 10R)
configuration. The mechanism is likely to follow that the metal
coordinates with the chelating ligand to form a rigid chiral
structure and acts as a Lewis acid to activate the aldehyde; the
primary amine reacts with cyclohexanone to form an enamine
attacking the activated aldehyde from the re-face to generate the
products (Fig. 2).
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In summary, we have developed a new class of primary
amine-metal Lewis acid cooperative bifunctional catalysts
using simple bidentate ligands. These bifunctional catalysts
displayed exceptionally high activity in the direct asymmetric
aldol reactions of ketones with both electron-rich and
electron-poor aldehydes. The enantioselectivities obtained
from these reactions are comparable with those catalyzed by
the best organocatalysts, and are much higher than those of
the tridentate ligand system. It is notable that these catalysts
possess both advantages of metal Lewis acid and organo-
catalysts, as requiring low catalyst loading and being water
tolerant. The in depth understanding of the coordination
chemistry of these bifunctional catalysts is currently under
investigation. The application of these enamine-metal Lewis
acid bifunctional catalysts to activate ketone acceptors
through a strong Lewis acid in aldol reactions as well as in
inverse-electron-demand hetero-Diels–Alder reactions are
under way, and will be reported in due course.
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We thank Professor Mike Novak for useful discussions.
Financial support was provided by Miami University.
Notes and references
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This journal is The Royal Society of Chemistry 2011
226 | Chem. Commun., 2011, 47, 224–226