A versatile Co(bisalen) unit for homogeneous and heterogeneous cooperative catalysis in the hydrolytic kinetic resolution of epoxides

Article abstract of DOI:10.1002/chem.200900030

A study was conducted to demonstrate the synthesis of a versatile Co(bisalen) unit for homogeneous and heterogeneous cooperative catalysis in the hydrolytic kinetic resolution of expoxides. The styryl-substituted unsymmetrical bisalen was synthesized by f

Full text of DOI:10.1002/chem.200900030

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DOI: 10.1002/chem.200900030
A Versatile CoACTHNUGTRNEUNG(bisalen) Unit for Homogeneous and Heterogeneous
Cooperative Catalysis in the Hydrolytic Kinetic Resolution of Epoxides
Krishnan Venkatasubbaiah,[a] Christopher S. Gill,[a] Tait Takatani,[b]
C. David Sherrill,[b] and Christopher W. Jones*[a, b]
Epoxides are versatile building blocks and extensively
used in the synthesis of organic compounds.[1] Asymmetric
catalysis has expanded the scope of these epoxides as valua-
ble intermediates, especially in the pharmaceutical industry.
The hydrolytic kinetic resolution (HKR) catalyzed by Co-
advantage, however, is that these catalysts are relatively dif-
ficult to recover and reuse, owing to their soluble nature
under reaction conditions.[22] Furthermore, it should be
noted that each of these systems represents a single opti-
mized and relatively complex catalyst derived from a multi-
step organic synthesis.
ACHTUNGTRENNUNG(salen) has emerged as a powerful, simple, and widely used
method for the generation of terminal epoxides in enantio-
merically pure form.[2–7] Mechanistic investigation of the
HKR reaction has shown a second-order kinetic dependence
on the catalyst, which is suggested to arise from the dual ac-
tivation pathway in the reaction. In the catalytic cycle, one
cobalt center is proposed to bind to the hydroxide and the
other activates the epoxide.[8] Different approaches have
been identified to enhance the activity relative to the mono-
meric catalyst, which include building oligomers,[9–11] den-
drimers,[12] polymers,[13–18] and encapsulating complexes in
nanocages.[19,20] Jacobsen and co-workers attached CoIII-
Simpler, more versatile approaches to cooperative salen
catalysis are needed. Furthermore, highly active, cooperative
CoACTHNUTRGNE(NUG salen) catalysts that are easily recoverable and recycla-
ble are exceedingly rare. In this vein, the nanocage approach
adopted by Li and co-workers[19] appears versatile and
works moderately well for small molecules, although it may
be difficult to use the nanocage systems for larger epoxides
due to the pore diameter reduction involved in the synthesis
of the constricted nanocages. Seeking a modular building
block for homogeneous and heterogeneous cooperative
salen catalysis, here we report a simple design for a styryl-
substituted unsymmetrical “bisalen” and demonstrate its
versatility in creating highly active, cooperative homogene-
ous and recyclable heterogeneous catalysts in the hydrolytic
kinetic resolution of epoxides.
ACHTUNGTRENNUNG(salen) to a dendrimer and showed improved reactivity due
to cooperativity.[12] Enhanced cooperativity in the HKR
using complexes confined in nanocages was suggested by Li
and co-workers.[19] Recently we reported a highly active un-
symmetrical macrocyclic oligomeric Co
(salen) for HKR
The styryl-substituted unsymmertrical bisalen (2) was syn-
thesized by following the one-pot protocol developed in col-
laboration with Weck and co-workers,[23] which employed
the condensation of two equivalents of HCl-protected dia-
mine, two equivalents of 3,5-di-tert-butyl-2-hydroxybenzal-
dehyde, and one equivalent of dialdehyde (1), in 38% yield
(Scheme 2). The formation of the bisalen (2) was confirmed
(Scheme 1).[21]
A key advantage of the oligomer, dendrimer, and macro-
cyclic oligomeric Co(salen) catalysts are the enhanced activ-
ities associated with their structures that allow for efficient
Co(salen):Co(salen) cooperative interactions. A distinct dis-
ACHTUNGTRENNUG
A
ACHTUNGTRENNUNG
1
by H and 13C NMR spectroscopy and FAB mass spectrome-
[a] Dr. K. Venkatasubbaiah, Dr. C. S. Gill, Prof. Dr. C. W. Jones
School of Chemical & Biomolecular Engineering
Georgia Institute of Technology
try ([M]+ =1267). Metalation using cobalt(II) actetate tetra-
hydrate with 2 in a dichloromethane/methanol mixture af-
forded the Co
mass spectrum of 3 showed a peak at m/z 1380, confirming
the formation of the intended Co(bisalen). The formation of
2 and 3 was further confirmed by using elemental analysis.
The versatile Co(bisalen) (3) can act as i) a soluble small
ACHTUNGTRENN(UNG bisalen) (3) in 88% yield. The MALDI-TOF
311 Ferst Drive, Atlanta, GA 30332 (USA)
Fax : (+1)404-894-2866
E-mail: christopher.jones@chbe.gatech.edu
AHCTUNGTRENNUNG
[b] T. Takatani, Prof. Dr. C. D. Sherrill, Prof. Dr. C. W. Jones
School of Chemistry and Biochemistry
AHCTUNGTRENNUNG
Georgia Institute of Technology
molecule catalyst (vide infra) or it (or 2) can be employed
as a versatile building block in the synthesis of ii) soluble
homogeneous copolymer complexes (5a and 5b), iii) insolu-
901 Atlantic Drive, Atlanta, GA 30332 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900030.
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Scheme 1. Representative examples of cooperative salen catalysts.
ble cross-linked polymeric resin
complex (6), or iv) insoluble
silica-supported complex (7), all
of which contain the coopera-
tive bisalen motif. Here we de-
scribe the realization of cooper-
ative CoACHTNUTRGNEUNG(bisalen) catalysts (i–
iii: Scheme 3).
To make the soluble, cooper-
ative, polymeric catalysts, the
styryl monomer 2 was co-poly-
merized by using styrene as a
co-monomer and azobisisobu-
tyronitrile (AIBN) as free-radi-
cal initiator in chloroben-
zene.[24,25] To illuminate the
effect of dilution of the bisalen;
two different monomer ratios
were used (2/styrene ratio: 3=
1:4 , 4=1:10). The polymers
were isolated in 75–80% yield
by reprecipitation from metha-
nol and characterized by using
1H NMR, 13C NMR, UV/Vis,
FT-IR spectroscopies, and GPC
analysis. The ratio of the bisa-
len monomer to styrene was
found to be 1:4 in 3 and 1:12 in
Scheme 2. Synthesis of the styryl bisalen.
1
4, as determined using H NMR
spectroscopy. The GPC analysis
relative to polyACTHNUTRGENUGN(styrene) stand-
ards gave a molecular weight
(Mw) and polydispersity (PDI)
of Mw=28680 and PDI=2.10
for 4a and Mw=17980 and
PDI=2.03 for 4b. Metalated
copolymers were synthesized by
the reaction of 4a or 4b with
cobalt(II) acetate tetrahydrate
in a dichloromethane/methanol
mixture. The Co content was
Scheme 3. CoACHTUNGTRENNUNG(bisalen) 3, copolymers 5a and 5b, and insoluble resin 6.
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Cooperative Catalysts for the Hydrolytic Kinetic Resolution of Epoxides
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determined by elemental analysis, which suggests that 93%
(5a) and 81% (5b) of the salen units were loaded with
cobalt. The insoluble resin (iii) was made by the copolymeri-
zation of 2 with divinylbenzene (DVB) in a ratio of 1 to 10.
Metalation of the resin with cobalt(II) acetate tetrahydrate
afforded the metalated resin 6. Elemental analysis indicated
that 80% of the salen units were metalated.
in conjunction with the LANL2DZ effective core potential
for Co and the 6-31G* basis for other atoms. The resulting
DFT structure allowed us to predict that our design can ac-
commodate structures in which two salens[27] are in very
close proximity and can cooperate as proposed in the transi-
tion state suggested by Jacobsen, Blackmond and co-work-
ers[8] in the bimetallic mechanism of HKR.
The active CoIII catalysts were made by aerial oxidation
The catalytic performance of the copolymers containing
the bisalen monomer are compared in Figure 1. The copoly-
of CoII precatalysts with the help of acetic acid and subse-
quently studied for the HKR of racemic epichlorohydrin.
The reactions were performed at a 0.02 mol% Co loading.
At this concentration, the styryl unsymmetrical bisalen (3-
mers 5a
bisalen 3AHCUTNGTRENNUNG
G
ACHTUNGTRNE(NUNG OAc) are as active as the molecular
copolymers does not reduce the activity; rather there is a
slight increase in the activity that is assumed to arise from
flexibility in the polymer backbone or decreased steric
crowding among the side chains, a phenomenon that we also
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
porting Information) gave only 13% ee over the same dura-
tion (Figure 1). This is a direct consequence of the coopera-
tive bimetallic pathway suggested for efficient HKR. Densi-
ty functional theory (DFT) computations were performed
by using the Jaguar suite of programs[26] to model the bind-
ing of hydroxide to one metal center and the epoxide to the
other center (Figure 2). We employed the BP86 functional
observed in our earlier work.[15] The insoluble resin 6
ACHTUNGTRENNUNG(OAc)
was also tested in the ring-opening reaction of epichlorohy-
drin, but at a slightly higher catalyst loading of 0.04 mol%.
The preliminary results suggest that the resin is also highly
active, achieving full conversion of one enantiomer in 5 h
(99% ee, conversion 52%). The recycling of the resin was
studied at the same loading, with the catalyst recovered by
simple filtration after each cycle, then regenerated and
reused (Table 1). The selectivity of the recycled catalyst re-
mained about the same after three cycles, but the reactivity
decreased (Figure 3).[28] To test whether the deactivation
arises due to leaching of catalyst, we analyzed the filtrate by
1
using H NMR spectroscopy and elemental analysis and the
results did not suggest there was leaching of ligand or metal.
To the best of our knowledge, this is one of the most active
Table 1. Recycling of catalyst 6
ACHTUNGTRNE(NUNG OAc) in the HKR of epichlorohydrin.
Cycle Loading [mol%] ee[a] [%] Epoxide ee[b] [%] Diol Conv.[b] [%]
1
2
3
0.04
0.04
0.04
99
99
99
93
90
83
52
53
55
[a] The ee corresponds to the enantiomeric excess of the unreacted epox-
ide determined by chiral GC. [b] Determined by chiral GC.
Figure 1. Kinetic plot of the HKR of epichlorohydrin using CoIII
complexes at 0.02 mol% loading.
ACHTUNGTRNE(NUNG salen)
Figure 3. Recycling of 6ACTHNUTRGNE(NUG OAc) in the HKR of epichlorohydrin at 0.04
Figure 2. BP86/6-31G*-LANL2DZ-optimized Co
G
mol% loading.
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C. W. Jones et al.
the excessive triethylamine were removed under vacuum. The residue
was dissolved in dichloromethane (50 mL), washed with water (2ꢂ
50 mL), and dried with magnesium sulfate. Flash chromatography of the
crude material on silica gel (10/90 ether/hexanes) afforded compound 2
as a yellow solid (1.02 g, 38%). 1H NMR (CDCl3): d=13.95 (s, br, 2H,
OH), 13.69 (s, br, 2H, OH), 8.33 (s, 2H, CH=N), 8.30 (s, 2H, CH=N),
7.33 (d, J=2.8 Hz, 2H, Ph), 7.23 (d, J=8.0 Hz, 2H, Ph), 7.18 (d, J=
1.6 Hz, 2H, Ph), 6.99 (d, J=2.4 Hz, 2H, Ph), 6.95 (d, J=2.0 Hz, 2H, Ph),
6.85 (d, J=8.0 Hz, 2H, Ph), 6.66 (dd, J=10.8, 18.0 Hz, 1H, CH=CH2),
5.69 (d, J=18.0 Hz, 1H, CH=CH2), 5.21 (d, J=11.2 Hz, 1H, CH=CH2),
3.85–3.76 (m, 4H, -CH2-), 3.49 (s, 4H, -CH2-), 3.34–3.32 (m, 4H, -CH2-),
2.47 (s, 4H, -CH2-), 1.98–1.71 (m, 12H, cyclohexyl), 1.49–1.41 (m, 40H,
cyclohexyl, CMe3), 1.25 (s, 18H, CMe3), 0.77 ppm (s, 3H, Me); 13C NMR
(100.6 MHz, CDCl3, 258C): d=171.4, 165.7, 165.1, 159.4, 157.9, 139.8,
137.3, 136.4, 136.3, 135.8, 135.7, 130.4, 130.3, 130.1, 126.7, 125.9, 122.7,
118.4, 117.7, 113.4, 72.3, 72.1, 67.4, 67.3, 40.6, 39.8, 38.4, 34.9, 34.7, 33.9,
33.1, 31.3, 29.4, 29.3, 24.2, 18.9 ppm; MS (ESI): m/z 1267.8309; HRMS
calcd: C81H111O8N4 1267.8396; found: 1267.8309; elemental analysis calcd
(%) for C81H110O8N4: C 76.77, H 8.68, N 4.42; found: C 77.04, H 8.68, N
3.99; IR (KBr): n˜ =3073, 2951, 2860, 1736, 1627, 1592, 1466, 1439, 1388,
1360, 1268, 1250, 1132, 1013, 849 cmÀ1; UV/Vis (CH2Cl2): lmax =255,
332 nm.
supported heterogenous CoACTHNURGTNE(NUG salen) catalysts that can be re-
cycled very easily by simple filtration.[29] A unique advantage
of our approach is that an array of catalysts with the same
bimetallic motif can be prepared, all of which operate in a
cooperative manner with high activity and selectivity.
To assess the versatility of the catalysts, we also tested the
catalytic activity of copolymer 5a
ACHTUNGERTN(NUNG OAc) with other terminal
epoxides (Table 2). For instance, the resolution of 1,2-epoxy-
Table 2. HKR of various terminal epoxides using 5aCAHTUNGTRENNUNG
Entry
R
1
2
3
nBu
CH2Cl 0.02
Ph 0.2
0.02
2
5
20
99
99
97
51
52
49
[a] The ee corresponds to the enantiomeric excess of the unreacted epox-
ide determined by chiral GC. [b] Determined by chiral GC.
hexane was completed in 2 h with 0.02 mol% of cobalt load-
ing, affording an enantiomeric excess of 99% (conversion
51%). In addition, the resolution of styrene epoxide was
complete in 20 h with 0.2 mol% loading, resulting in an en-
antiomeric excess of 97% (conversion 49%).
In summary, we developed a new, versatile bisalen motif
that can be incorporated into a variety of homogeneous and
heterogeneous cooperative catalysts. The bisalen styryl mo-
nomer can be used to prepare numerous polymeric catalysts
with variable global Co loadings but a common local paired
Acknowledgements
The US DOE Office of Basic Energy Science through Catalysis Contract
No. DEFG02–03ER15459. C.W.J. acknowledges ChBE at GT for the J.
Carl & Shiela Pirkle Faculty Fellowship.
Keywords: epoxides
heterogeneous catalysis
·
homogeneous
immobilization
catalysis
·
·
·
kinetic
resolution · polymers
Co concentration. The catalytic activity of the CoACTHNUTRGENUG(N bisalen)-
derived catalysts in the HKR of epoxides was tested and in
all cases the bisalen catalysts are superior to the monomeric
catalyst. The activity of bisalen itself is comparable with
other highly active oligomeric, polymeric, and dendritic
salens, but its versatility—it can be used to make soluble
polymeric, insoluble polymeric, or insoluble oxide-supported
catalysts—makes it unprecedented among cooperative salen
catalysts. The design also allowed us to model the bisalen
with hydroxide binding to one metal center and an epoxide
to the neighboring metal center. Further studies exploring
cooperative catalytic mechanisms through DFT computa-
tions and optimization of the catalyst recycle and regenera-
tion are currently in progress.
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Experimental Section
Synthesis of bisalen (2): A 250 mL flask was charged with (1R,2R)-1,2-di-
aminocyclohexane mono(hydrogen chloride) (0.64 g, 4.26 mmol), activat-
ed 4 ꢁ molecular sieves (1.00 g), and anhydrous methanol (50 mL). 3,5-
Di-tert-butyl-2-hydroxybenzaldehyde (1.00 g, 4.26 mmol) was added in
one portion and the reaction mixture was stirred at room temperature
for 4 h. A solution of 1 (1.37 g, 2.13 mmol) in anhydrous dichloromethane
(50 mL) was then added to the reaction system, followed by the slow ad-
dition of triethylamine (1.18 mL, 8.53 mmol). After the reaction mixture
was stirred at room temperature for an additional 4 h, all solvents and
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Cooperative Catalysts for the Hydrolytic Kinetic Resolution of Epoxides
COMMUNICATION
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[28] C. S. Gill, K. Venkatasubbaiah, N. T. S. Phan, M. Weck, C. W. Jones,
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[29] It should be noted that the homogeneous oligomeric (ref. [11]), den-
[22] It should be noted that the homogeneous, small molecule CoACHTNUTGRNEUNG(salen)
has been recycled by removing the volatile reactants and products
and adding fresh reagents to the catalyst in solution (see ref. [5,7,14]
for more details). This method is obviously restricted to reagents
with suitable volatility.
dritic (ref. [12]), and macrocyclic (ref. [21]) Co
ACHTUNGTREN(NUNG salen)s may show su-
perior activity over 6 owing to their soluble nature.
[23] M. Holbach, X. L. Zheng, C. Burd, C. W. Jones, M. Weck, J. Org.
Chem. 2006, 71, 2903.
Received: January 6, 2009
Published online: March 5, 2009
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