Self-assembled dinuclear cobalt(II)-salen catalyst through hydrogen-bonding and its application to enantioselective nitro-aldol (Henry) reaction

Article abstract of DOI:10.1021/ja807221s

Novel chiral dinuclear Co(II)-salen catalysts self-assembled through the pyridone/aminopyridine hydrogen-bonding pair have been developed. The self-assembled dinuclear Co(II)-Salen catalyst results in significant rate acceleration (48 times faster rate) a

Full text of DOI:10.1021/ja807221s

Published on Web 11/14/2008
Self-Assembled Dinuclear Cobalt(II)-Salen Catalyst Through Hydrogen-Bonding
and Its Application to Enantioselective Nitro-Aldol (Henry) Reaction
Jongwoo Park, Kai Lang, Khalil A. Abboud, and Sukwon Hong*
Department of Chemistry, UniVersity of Florida, P.O. Box 117200, GainesVille, Florida 32611-7200
Received September 11, 2008; E-mail: shong@chem.ufl.edu
Cooperative reactivity between multiple metal centers in close
proximity is a common phenomenon for enzymatic systems,1
whereas most synthetic homogeneous transition metal catalysts
consist of one metal center. Recently, there have been growing
efforts to develop bimetallic catalysts enabling cooperative, simul-
taneous activation of both an electrophile and a nucleophile in
asymmetric catalysis.2 For example, chiral metal salen complexes
developed by Jacobsen and co-workers are highly efficient catalysts
for the asymmetric epoxide opening reactions, wherein two metal
centers are involved in the transition state.3 This discovery led to
the development of a number of covalently linked macromolecular
salen structures4 showing improved reactivity as well as enanti-
oselectivity.
The self-assembly or supramolecular approach using reversible
noncovalent bonding interactions5 such as hydrogen bonding6 is a
highly attractive strategy which enables rapid construction of
multinuclear systems in solution via self-assembly of monomeric
units. Herein we wish to report a novel dinuclear Co(II)-salen
catalyst self-assembled through complementary hydrogen bonding
interactions which results in significant enhancement of reaction
rates and enantioselectivity of Henry reactions. Our catalyst design
features two 2-pyridone/aminopyridine hydrogen bonding pairs6e,f
to create self-assembled dimers in solution (Figure 1). The
unsymmetrical (2a) and symmetrical (2b-c)7 salen ligands were
prepared by condensation of salicylaldehydes and (R,R)-1,2-
cyclohexane diamine (Figure 1).8 Cobalt (II) complexes 1a-d were
prepared by reacting the corresponding salens with Co(OAc)2 ·4H2O
under argon.
nitronate ions can bind to the metal center and the reaction proceeds
in aprotic solvents such as CH2Cl2.
Newly prepared Co(salen) catalysts were tested in the reaction
of o-methoxybenzaldehyde and nitromethane in the presence of 2
mol% of DIPEA (Table 1). We were pleased to find that the
unsymmetrical Co(salen) catalyst 1a afforded the nitroaldol adduct
6a in 87% yield and 96% ee (entry 1), whereas monomeric Co(II)
catalyst 4 and Co(III) catalyst 4(OAc)11 gave the product in less
than 11% yield and 55-64% ee under the same conditions (entries
8-9). Symmetrical Co(salen)s (1b and 1c) gave the product in
similarly low yields and slightly improved ee’s (entries 5-6). In
addition, loss of enantioselectivity was observed when self-
assembled catalyst (1a) or monomeric catalyst (4) was used in
MeOH (entries 3 and 10). However, when an equimolar mixture
of Co(salen)s 1b and 1c was used as a heterodimeric catalyst, 87%
ee was obtained, but the yield was low (18%) as they are used
alone, suggesting that those two symmetrical salens would form a
relatively weak dimeric species (entry 7).12 When 100 mol% of
base were used, the reaction was accelerated with the slight loss of
enantioselectivity (entry 2). Interestingly, when free ligand 2a was
added to the reaction mixture, yield was lowered noticeably,
suggesting that 2a might be a competitive inhibitor for the bimetallic
species formation (entry 4).
Table 1. Henry Reaction of o-Methoxybenzaldehydea
DIPEA
(mol%)
time
(h)
yieldb
(%)
eec
(%)
entry
Co(salen)
solvent
1
2
3
4
5
6
7
8
1a
1a
2
100
2
2
2
2
2
2
2
CH2Cl2
CH2Cl2
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
CH2Cl2
90
40
40
90
90
90
90
90
90
40
90
87
91
89
59
12
16
18
11
96
91
25
96
72
69
87
55
64
5
1a
1a + 2ad
1b
1c
1b + 1ce
4
9
10
11
4(OAc)
4
1d
<10
93
14
2
2
70
a The reaction was carried out at 0.25 mmol scale in CH2Cl2 (1.0
mL) or MeOH (1.0 mL) at -30 °C. b In cases of low yield, only the
unreacted starting material was recovered. c Ee was determined by chiral
HPLC. d Salen ligand 2a (6 mol%) was used as an additive. e 1b (1
mol%) and 1c (1 mol%) were used as an equimolar mixture.
Figure 1. Structure of self-complementary dinuclear Co(salen) complex
and symmetrical Co(salen) complexes.
The Henry reaction is an important C-C bond forming reaction,
and many excellent asymmetric catalytic systems have been
developed.9 Recently, the Yamada group10a and the Skarz˙ewski
group10b reported that Co(II)- and Cr(III)-salen complexes can
catalyze this reaction in the presence of external base. We
envisioned that this reaction could serve as an ideal model system
to test our new self-assembled catalyst because both aldehydes and
The reaction scope was then studied by varying aryl aldehyde
substrates using the self-assembled Co(salen) 1a (Table 2). Slightly
more concentrated conditions were used to further reduce the
reaction time for less reactive substrates. High enantiomeric excesses
(81-96% ee) and good to excellent yields (65-99%) were obtained
for various aryl aldehydes.
9
16484 J. AM. CHEM. SOC. 2008, 130, 16484–16485
10.1021/ja807221s CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
bonding was confirmed by the X-ray structure and 1H experiments.
A bimetallic mechanism is suggested by the kinetic experiment
(Rate [catalyst]2). This result proves the validity of novel self-
assembly based approaches toward the efficient construction of
chiral bimetallic catalyst systems. Further modifications of ligand
structure to allow formation of heterobimetallic dimers are in
progress.
Table 2. Scope of Aromatic Aldehydes of the Self-Assembled
Cobalt(salen) Catalyzed Asymmetric Henry Reactiona
Co(salen)
(mol%)
time
(h)
yield
(%)
eeb
(%)
entry
aldehyde
1
2
3
4
5
6
7
8
o-MeOC6H4 (5a)
o-ClC6H4 (5b)
o-FC6H4 (5c)
2
2
2
2
2
5
2
2
48
14
14
40
40
110
40
65
89
97
97
99
65
77
92
88
96
93
94
82
90
81
91
87
Acknowledgment. We thank Prof. Ron Castellano for helpful
discussions and the University of Florida for financial support.
p-CF3C6H4 (5d)
p-FC6H4 (5e)
Supporting Information Available: Experimental details, NMR
spectra for new compounds, kinetic data, nonlinear curve-fitting
analysis, and HPLC analysis data (pdf), and X-ray crystallographic data
for 3a (cif). This material is available free of charge via the Internet at
http://pubs.acs.org.
p-MeOC6H4 (5f)c
1-naphthyl (5g)
2-naphthyl (5h)
a The reaction was carried out at 0.25 mmol scale in CH2Cl2 (0.25
mL) at -30 °C. b Ee was determined by chiral HPLC. c 10 mol% of
DIPEA were used.
References
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To confirm our hypothesis that the bimetallic activation plays a
critical role in the Co(salen) catalyzed Henry reaction, kinetic studies
were performed by monitoring initial reaction rates (consumption
of o-methoxybenzaldehyde) by HPLC. Rate laws were found to
be second order in cobalt concentration (Rate ) kobs[Co-Salen]2)
for both monomeric (4) and self-assembled Co(salen) complexes
(1a), indicating that two molecules of 4 and 1a are involved in the
transition state. Rate constant kobs of self-assembled catalyst 1a is
289 M-1 h-1, which is 48 times larger than that of monomeric
cobalt-salen catalyst 4 (kobs ) 6.02 M-1 h-1).8 The rate acceleration
by 1a can be rationalized by the facile formation of a stable dimer
of 1a through hydrogen bonding in nonpolar media.
The X-ray structure of Ni(Salen) complex 3a clearly showed
self-assembly through hydrogen bonding (Figure 2). The self-
assembled dimer adopts the “head-to-tail” conformation where the
metal-metal distance is 4.054 Å. To verify the hydrogen-bonding
event in solution, 1H experiments were performed with metal-free
salen ligand 2a.8,13 When 25% v/v CD3NO2 in CDCl3 was used as
a media which is similar to the actual Henry reaction conditions,
the NH proton signal of the pivalamide group and the signals of
three protons of the pyridine ring in the ligand 2a were changed
upon variation of concentration (0.14-19.09 mM).14 The dimer-
ization constant Kdim of self-assembled salen ligand 2a was
estimated as 53 ( 21 M-1 by using nonlinear curve fitting
methods.15 These solution-phase 1H experiments confirm the
hydrogen-bonding interaction in the pyridone-aminopyridine func-
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Figure 2. X-ray structure of self-assembled Ni(Salen) complex 3a•3a. The
Ni-Ni distance is 4.054(2) Å. The hydrogen-bonding donor-acceptor
distances are 2.858(7) for N-H--O and 2.922(7) for N--H-N. Disorders
on the cyclohexane rings were removed for clarity.8 Thermal ellipsoids are
drawn at the 50% probability level.
(14) The NH signal of 2-pyridone was not observed due to the peak broadening
in this solvent system.
In conclusion, we have developed a chiral bimetallic Co(II)-
salen catalyst self-assembled through hydrogen bonding, which
results in significant rate acceleration as well as excellent enanti-
oselectivity in Henry reaction. The self-assembly through hydrogen
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