Highly recyclable self-supported chiral catalysts for the enantioselective α-hydrazination of β-ketoesters

Article abstract of DOI:10.1002/cctc.201300395

Multitopic chiral copper complexes based on bis(oxazoline) have been applied in the enantioselective α-hydrazination of β-ketoesters. High yields and excellent enantioselectivities were obtained. Furthermore, the catalytic systems have been recovered in u

Full text of DOI:10.1002/cctc.201300395

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DOI: 10.1002/cctc.201300395
Highly Recyclable Self-Supported Chiral Catalysts for the
Enantioselective a-Hydrazination of b-Ketoesters
Maria Torres, Aline Maisse-FranÅois, and Stꢀphane Bellemin-Laponnaz*[a]
Multitopic chiral copper complexes based on bis(oxazoline)
have been applied in the enantioselective a-hydrazination of
b-ketoesters. High yields and excellent enantioselectivities
were obtained. Furthermore, the catalytic systems have been
recovered in up to ten cycles without loss of activity or enan-
tioselectivity. The formation of coordination polymers [polytop-
ic ligand–Cu]n has been confirmed by UV/Vis titrations. Signifi-
cant metal leaching was observed on increasing the topicity of
the ligand. The nature of the catalyst was studied by nonlinear
effect experiments.
Introduction
Asymmetric catalysis is a privileged approach for the produc-
tion of enantiopure products. Today a large number of chiral
catalytic processes may deliver products with very high enan-
tiomeric excesses (ee) and some have been applied on an in-
dustrial scale. An example is the Tagasako process for the pro-
duction of (À)-menthol that involves a Rh/2,2’-bis(diphenyl-
phosphino)-1,1’-binaphthyl (BINAP) catalyst (1500 tonsyearÀ1).[1]
Another example is the manufacture of (S)-metolachlor that
uses an Ir/Josiphos catalyst (>10000 tonsyearÀ1).[2] These ho-
mogeneous catalysts have thus shown synthetic utility because
of their high activity and selectivity. However, homogeneous
catalytic systems frequently exhibit lower activity and suffer
from two drawbacks: 1) possible product contamination: in
particular, metal contamination in active pharmaceutical ingre-
dients or fine chemicals is a serious concern, and the remain-
ing metal traces must be reduced to ppm amounts in the final
products and 2) the inability to reuse the chiral catalyst. Cata-
lytic systems that allow easy separation from the reaction mix-
ture and efficient recycling are highly desirable because of the
high cost of both the chiral ligand and the metal.
compete with their homogeneous catalysis analogues as the
immobilization step usually requires structural modifications of
the complex that lower the activity and/or selectivity. Overall,
this highlights the important influence of the catalyst support,
which is yet to be understood.
In this context, a strategy that combines the advantages of
both techniques (homogeneous and heterogeneous) appears
desirable, that is, to associate the selectivity and activity of-
fered by homogeneous catalysis with the easy recycling per-
mitted by a heterogeneous system. In this sense, the selective
assembly of multitopic ligands and metals into homochiral
metal–organic coordination polymers (i.e., a self-supporting
strategy; Scheme 1) may be considered as an appealing ap-
Scheme 1. The principle of self-supported catalysis.
Immobilized homogeneous asymmetric catalysis is an attrac-
tive way to solve such problems, and efforts have been under-
taken in this field. Over the past few decades, several strategies
have been developed for the immobilization of homogeneous
catalysts; these include immobilization on a solid support (in-
organic, organic, polymer, or dendrimer) or the use of noncon-
ventional media (phase-transfer catalysis, fluorous phase sepa-
ration, ionic liquids, supercritical CO2).[3,4] Although some of
these systems have demonstrated good performances (enan-
tioselectivity, activity, stability, or recycling ability), very few can
proach.[5] In such systems, the catalyst remains heterogeneous
in its resting state at the end of the reaction and is dissolved
in the reaction medium in its catalytically active state. There
are at least two prerequisites to develop this type of catalyst.
First, the metallopolymer obtained by a self-assembly process
should be able to undergo a reversible polymerization/depoly-
merization process, such a feature is primarily controlled by
the strength of the bonding interactions. Second, as the trans-
formation of the inactive resting state into the active species
occurs by depolymerization (i.e., partial decoordination) of the
system, it is important that all monomeric active species
should be equivalent. In other words, the effective symmetry
of a coordinated ligand at the metal center must always be
the same. In this regard, highly symmetric bis(oxazoline) li-
gands have been proved to be interesting tools to develop
self-supported chiral catalysts. Garcia and collaborators report-
ed the first example of oxazoline-based self-supported cata-
[a] M. Torres, Dr. A. Maisse-FranÅois, Dr. S. Bellemin-Laponnaz
Institut de Physique et Chimie des Matꢀriaux de Strasbourg
Universitꢀ de Strasbourg, CNRS, UMR 7504
23 rue du Loess, BP 43, F-67034 Strasbourg Cedex 2 (France)
Fax: (+33)388107246
E-mail: bellemin@unistra.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201300395.
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lysts in 2008.[6,7] Ditopic chiral ligands that bear azabis(oxazo-
line) moieties have been successfully used in the cyclopropa-
nation reaction of alkenes with ethyl diazoacetate, the allylic
oxidation of cycloalkenes with peroxoesters as well as the ni-
troaldol reaction, and the catalyst could usually be recycled
without loss of activity and selectivity.[6,8–10]
In this work, we describe the application of CuII complexes
supported by polytopic ligands (bis-, tris-, and tetratopic) as
catalysts for the enantioselective a-hydrazination of b-ketoest-
ers and their recovery by precipitation of the corresponding
metallopolymers. Our investigations showed that ditopic li-
gands are best suited and that the use of tri- or tetratopic li-
gands did not improve the efficiency of the catalytic reaction.
Excellent results (up to 99% ee and 99% yield) could be ach-
ieved along with easy recycling of the catalyst (up to ten
times). To gain insights into these dynamic systems, we also
conducted UV/Vis titrations of the metallopolymer formation,
catalyst leaching investigations, and nonlinear effect (NLE)
studies.
As a test reaction, we investigated the enantioselective a-hy-
drazination of b-ketoesters, a reaction of interest for the syn-
thesis of b-hydroxy-a-amino acids.[14] CuII salts in combination
with bisoxazoline ligands have been shown to be effective cat-
alysts for such reactions.[15]
The reaction of ethyl-2-methylacetoacetate with dibenzyla-
zodicarboxylate was used as a reference reaction for our cata-
lyst screening.[16] Some representative results are presented in
Table 1. By using 4.0 mol% of 1/Cu(OTf)2 in dichloromethane
Table 1. Enantioselective a-hydrazination of ethyl-2-methyl acetoacetate
catalyzed by Cu(OTf)2/ligand.[a]
Ligand
iPr-Me2Box
Yield [%]
ee [%]
1
2
3
4
5
6
80
95
83
95
83
83
54
58
78
93
82
77
iPr-MeBnBox
iPr-DiBox
Ph-DiBox
iPr-TriBox
iPr-TetraBox
Results and Discussion
[a] Experimental conditions: 4.0 mol% cat. Cu(OTf)2, 16h, 08C. Yields deter-
mined by 1H NMR spectroscopy by using an internal standard. Enantio-
meric excesses were determined by HPLC using Chiralcel AD column.
Ligand design and catalytic studies
The chiral ligands synthesized and used in the present study
are shown in Scheme 2. (S)-Valinol and (R)-phenylglycinol were
used to introduce groups with different steric bulk. Ditopic li-
gands 3 and 4 were synthesized in one step from methylbi-
as the solvent, an ee of 54% (80% yield) was observed at 08C
under air. The introduction of the benzyl group in the bis(oxa-
zoline) ligand 2 leads to a 58% ee and an increase of the reac-
tion yield (95%). With the di-, tri-, or tetratopic ligands, which
all contain isopropyl substituents, the catalytic results were
slightly improved to approximately 80% ee of the resulting
compounds, and the three systems were found to behave with
a similar efficiency (83% yield).[17] Phenyl substituents on the
oxazoline afforded the best results; thus, 93% ee and 95%
yield were observed upon using 4 as the supporting ligand.
We next compared the recycling of the catalyst with mono-,
di-, tri-, and tetratopic ligands. With the isopropyl-substituted
ligands, moderate enantiomeric excesses were observed. To
study the effect of the varying catalyst environments, a reaction
with moderate ee should be more informative, allowing a priori
an increase or decrease of the enantioselectivity. The results
are summarized in Table 2. For the catalytic investigations, di-
ethyl ether was added to the reaction media at the end of
each run, which led to the instantaneous precipitation of the
catalyst. The solid was then recovered, washed with diethyl
ether, dried, and then used again for another catalytic run.
Only one catalytic run could be conducted with the monotopic
ligands 1 or 2 as the catalytic system could not be recovered
at the end of the reaction. Notably, we could perform up to
eight cycles with the system with ditopic 3 with no significant
alteration in enantioselectivity and yield. The use of the system
with 5 led to a different outcome. After three runs, we ob-
served a drop of efficiency of the catalyst. This tendency was
even more pronounced with the tetratopic system 6. A signifi-
Scheme 2. Structures of the chiral ligands 1–6.
s(oxazolinyl)methane derivatives[11] by deprotonation followed
by reaction with 1,4-bis(bromomethyl)benzene.[12] The same
straightforward synthesis was used to access the tri- and tetra-
topic ligands 5 and 6. The monotopic ligands dimethylbis(oxa-
zoline) 1 and methylbenzylbis(oxazoline) 2 were used for com-
parison as they are structurally similar to the polytopic ligands
developed in this study.[13]
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elemental analysis was consistent with the formation
of the metallopolymer if the ditopic ligands 3 or 4
were used. However, the results were disappointing
with the tri- or tetratopic ligands, which did not give
the appropriate ligand/Cu molar ratio.
Table 2. Enantioselective a-hydrazination of ethyl-2-methyl acetoacetate catalyzed by
Cu(OTf)2/ligand and evaluation of the recycling.[a]
Despite numerous attempts, we were unable to
grow X-ray-quality single crystals of the metallopoly-
mers of Cu complexes of the multitopic ligands 3–6.
Unfortunately, we were unable to structurally charac-
terize such polymeric species. However, we isolated
a tetrameric CuII species (7) that bears ligand 6. The
reaction of four equivalents of CuCl2 with 6 in di-
chloromethane led to the formation of crystals suita-
ble for X-ray diffraction studies (Scheme 3).
In the solid state, 7 contains four bis(oxazoline)–Cu
units, two of which are located on one side of the
plane formed by the benzene ring and two on the
other side (Figure 1). Each Cu atom is in a distorted
square-planar coordination environment. The angle
between the Cl-Cu-Cl plane and the N-Cu-N plane
lies between 48.7 and 51.58. The average Cl-Cu-Cl
and N-Cu-N bond angles appear to be 99.7 and
89.38, respectively. The CuÀN and CuÀCl bond
lengths are in the range 1.942(9)–1.998(9) and
2.205(5)–2.243(3) ꢂ, respectively, and are consistent
1
[a] Experimental conditions: 4.0 mol% cat. Cu(OTf)2, 16h, 08C. Yields determined by H
NMR spectroscopy by using an internal standard. Enantiomeric excesses were deter-
mined by HPLC using Chiralcel AD column.
cant decrease of both the yields and the ee values
was observed after the first recycling (i.e., during the
second run). Overall, in the present case, increasing
the topicity of the ligand may be detrimental for the
efficient recycling of the catalytic system. From these
screening
experiments,
ditopic
bis(oxazoline)
emerged as the ligand of choice for further studies.
Having identified 3 and 4 as the most efficient sys-
tems for the enantioselective a-hydrazination of b-ke-
toester reactions, the scope with 4 as the ligand was
explored. Excellent results were demonstrated for
a series of acyclic and cyclic b-ketoesters. The sub-
strates were all reacted with dibenzylazodicarboxy-
late in the presence of 4.0 mol% of Cu(OTf)2/4 cata-
lyst in dichloromethane at 08C under air. At the end
of each reaction, diethyl ether was added to allow isolation of
the catalyst by simple decantation and reuse without further
purification in the next cycle. Acyclic b-ketoesters with alkyl
(Me, nBu) or benzyl substituents were tested as well as cyclic
b-ketoesters (five- and six-membered ring size) as shown in
Table 3. Excellent conversions and enantiomeric excesses could
be obtained and six to ten runs could be conducted as a func-
tion of the substrate.
Scheme 3. Synthesis of 7 from 6.
with previously published values.[18] A schematic view of the
orientation of the four Cu–bis(oxazoline) moieties is shown in
Figure 2. As a result of the rather flexible linker, each chelating
ligand points away from its nearest neighbors.
To further characterize the metallopolymers, we conducted
UV/Vis titration experiments. It is known that the formation of
a linear metallopolymer can be confirmed by the exact stoi-
chiometric ratio of the metal ion to ditopic ligand.[19] We first
studied the assembly between ditopic ligand 3 and Cu(OTf)2
by UV/Vis titration. The intensity of the band at 295 nm as
a function of added Cu is shown in Figure 3. The band increas-
es up to a ratio of 1:1, which indicates the formation of the
metallopolymer (Figure 1a). The titration experiment between
the tritopic ligand 5 and Cu(OTf)2 revealed a maximum intensi-
ty at a metal-to-ligand ratio of 1.5:1, which is again consistent
Structural studies of the catalysts
As the recoverability of the catalyst may be directly dependent
on its structure, we decided to conduct some structural studies
on our systems. We first analyzed the catalytic system that was
precipitated at the end of the run by elemental analysis. The
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Table 3. Enantioselective a-hydrazination of b-ketoesters catalyzed by Cu(OTf)2/4 and recycling in CH2Cl2 at 08C (16 h).[a]
[a] Experimental conditions: 4.0 mol% cat. Cu(OTf)2, 16h, 08C. Yields determined by 1H NMR spectroscopy by using an internal standard. Enantiomeric ex-
cesses were determined by HPLC using Chiralcel AD, OD, or AS column.
Figure 2. Schematic orientation of the four Cu–bis(oxazoline) units in 7.
Figure 1. Molecular structure of 7. Selected bond lengths [ꢂ] and angles [8]:
Cu(2)ÀCl(3), 2.242(4); Cu(2)ÀCl(4), 2.230(4); Cu(2)ÀN(3), 1.972(9); Cu(2)ÀN(4),
6 was followed by UV/Vis titration (Figure 3c). Interestingly,
1.983(9); N(3)-Cu(2)-N(4), 89.6(4); Cl(3)-Cu(2)-Cl(4), 100.64(18); N(3)-Cu(2)-
a maximum intensity was observed after the addition of more
than 2.5 equivalents of Cu(OTf)2, whereas only two equivalents
should be sufficient to form the expected metallopolymer. This
result suggests that the orientation of the four bis(oxazoline)
units may not allow effective complexation with the metal salt.
Cl(4), 97.9(3).
with the formation of the corresponding metallopolymer (Fig-
ure 3b). Finally, complexation of Cu with the tetratopic ligand
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2:1 ratio, respectively. Diethyl ether was added, and a turquoise
precipitate formed instantly. The supernatant was removed
and analyzed by inductively coupled plasma atomic-emission
spectroscopy (ICP-AES). This established a loss in the amount
of Cu of 3.9% with 3, 5.7% with 5, and 8.4% with 6. The topic-
ity of the ligand thus strongly affects the level of leaching,
which is consistent with the UV/Vis titration experiments. Over-
all, the elemental analysis of the solids along with the UV/Vis
titrations and the Cu leaching investigations are consistent
with the best recyclability performance observed for the ditop-
ic ligands 3 and 4.
Nonlinear effects
Additional information regarding the aggregation of the cata-
lytically active species may be gained from experiments in
which the ee of the starting ligand was varied.[20] A series of ex-
periments was performed to determine whether NLEs would
be observed, and a significant negative nonlinear relationship
between the ee of the product and that of the ligand was
found (Figure 4). The metallopolymer is expected to serve as
Figure 4. Enantiomeric excess of the product of ethyl-2-methyl acetoacetate
with dibenzylazodicarboxylate as function of the enantiomeric excess of the
chiral auxiliary 3 to show a negative NLE (4.0 mol% 3/Cu(OTf)2, 08C, CH2Cl2,
16 h).
a catalytically inactive reservoir and a negative NLE may be ob-
served only by the preferential formation of a homochiral me-
tallopolymer.[21] The steric demand and orientation of the oxa-
zoline substituents are the critical factors that determine the
formation of the homoleptic species. As CuII salts have
a strong tendency to form a sixfold coordination geometry in
a distorted octahedral environment (Jahn–Teller effect), the for-
mation of homochiral homoleptic species with ligands in the
equatorial position is expected to be favored.[22] The observa-
tion of a (À)-NLE is thus consistent with the preferential forma-
tion of a homochiral metallopolymer. Moreover, the perturbed
behavior is indicative of a complicated structure, which could
not be modeled by the simple mathematical models devel-
Figure 3. Plot of the absorption at 295 nm as a function of added Cu(OTf)2
(in MeOH at room temperature): a) 3, b) 5, c) 6.
Indeed, an important structural consideration here is that the
bis(oxazoline) moieties should be oriented in such a way that
they allow all Cu atoms to form homoleptic complexes. As de-
duced from the molecular structure in the solid state (Figures 1
and 2), it is apparently very difficult to reach such an unbroken
framework, if not impossible.
This observation was correlated with Cu leaching. We react-
ed Cu(OTf)2 with iPr-based ligands 3, 5, and 6 in a 1:1, 3:2, and
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was added followed by the b-ketoester (21.2 mL, 0.15mmol). The
resulting mixture was cooled to 08C, and dibenzylazodicarboxylate
(54.0mg, 0.18mmol) was added dropwise. After 16h at 08C, diethyl
ether was added, and a precipitate was formed instantly. The or-
ganic phase was isolated, concentrated, and the product was puri-
fied by flash chromatography (AcOEt/cyclohexane) and analyzed
by using chiral HPLC (93% ee, 98% yield). The catalyst recovered
by decantation was dried and reused in a new catalytic run. Ele-
mental analysis of the precipitated catalyst Cu(OTf)2–4: calcd (%)
for C50H46CuF6N4O10S2 (1104.59): C 54.37, H 4.20, N 5.07; found C
54.46, H 4.37, N 5.31. Elemental analysis of the precipitated catalyst
Cu(OTf)2–3: calcd (%) for C38H54CuF6N4O10S2 (968.52): C 47.12, H
5.62, N 5.78; found C 47.34, H 5.78, N 5.97.
oped by Kagan. A bell-shaped curve suggests a degree of ag-
gregation of at least three monomer units (i.e., a ML3 model or
more).[23]
Conclusions
We have described the synthesis of di-, tri-, and tetratopic bi-
s(oxazoline)-based ligands and the formation of their coordina-
tion polymers with Cu. These systems were able to act as effi-
cient self-supporting catalysts in the enantioselective a-hydra-
zination of b-ketoesters, a reaction of interest for the synthesis
of b-hydroxy-a-amino acids. With the ditopic ligand 4 and
Cu(OTf)2, the reactions proceeded with 4.0 mol% of the cata-
lyst to give the products in excellent yields and high enantio-
meric excesses. Easy recovery of the catalyst has been demon-
strated in up to ten cycles without loss of activity or enantiose-
lectivity. Interestingly, the increase of the topicity of the ligand
(i.e., tri- or tetratopic bis(oxazoline)) does not improve the re-
cycling efficiency of the system and more catalyst leaching
was observed in this case, in agreement with UV/Vis titration
data. Finally, the nature of the catalyst system has been stud-
ied by nonlinear effect experiments, which reveal that the reac-
tion mechanism most likely involves an equilibrium between
the catalytically inactive homochiral metallopolymers and the
active monomeric species.
Synthesis of (S)-iPr-DiBox (3). General Procedure
1,1’-Bis[(4S)-4,5-dihydro-4-isopropyloxazol-2-yl]ethane (3.96 mmol,
1 g) was dissolved in dry tetrahydrofuran (25 mL). A solution of
1.6m nBuLi in hexane (4.31 mmol, 2.7 mL) was added dropwise at
À788C. After stirring for 15 min, the cold bath was removed and
a,a’-dibromo-p-xylene (1.96 mmol, 517.3 mg) was added. The mix-
ture was then stirred at RT for 12 h. The resulting mixture was
washed with saturated NH4Cl solution, and the aqueous phase was
extracted with dichloromethane. The combined organic phases
were dried over Na2SO4. Evaporation of the solvent gave a colorless
oil, which was purified by silica-gel column chromatography
(AcOEt/MeOH, 95:5) to yield a colorless viscous oil (1.56 mmol,
1
948 mg, 80%).[a]D25 =À0.81 cm3 gÀ1 dmÀ1 (c=0.5 in CHCl3); H NMR
(300 MHz, CDCl3): d=7.03 (s, 4H, Harom), 4.22 (dt, 3J=8.0 Hz, 3J=
1.3 Hz, 4H, ÀNCH), 4.05–3.90 (m, 8H, ÀOCH2), 3.24 (s, 4H, ÀCH2),
1.84–1.67 (m, 4H, ÀCH(CH3)2), 1.40 (s, 6H, ÀC(CH3), 0.94–0.80 ppm
(m, 24H, ÀCH(CH3)2); 13C{1H} NMR (300 MHz, CDCl3): d=167.6 (N=
CO), 134.9 (ÀCarom), 130.1 (ÀCarom), 72.0, 71.6 (ÀNCH), 70.1, 69.8 (À
OCH2), 43.3 (ÀCCH3), 41.8 (ÀCH2), 32.5, 32.2 (ÀCH(CH3)2), 21.2 (À
C(CH3), 18.8, 18.7, 17.9, 17.5 ppm (ÀCH(CH3)2); IR (KBr): n˜ =
1658 cmÀ1 (s, C=N); MS (ESI+): m/z: 607.42 [M+H]+; elemental anal-
ysis calcd (%) for C36H54N4O4 (606.84): C 71.25, H 8.97, N 9.23;
found C 70.97, H 8.89, N 9.21.
Experimental Section
General Considerations
All reactions (except catalytic runs) were performed under an inert
atmosphere of Ar or N2 using standard Schlenk techniques. Sol-
vents were purified and degassed by standard procedures. All re-
agents were used without further purification. 1H and 13C NMR
spectra were recorded by using a Bruker Avance 300 spectrometer
using the residual solvent peak as a reference (CDCl3: dH =
7.26 ppm; dC =77.16 ppm) at 298 K. HRMS (ESI) analyses were per-
formed by using a microTOF instrument (Bruker Daltonics). HPLC
analyses were performed by using a Gilson apparatus (UV-VIS156/
321 PUMP) with Chiralcel Daicel columns (AD, OD, AS) using n-
hexane/iPrOH eluents. Crystal data were collected at 173 K with
MoKa graphite-monochromated (l=0.71073 ꢂ) radiation by using
a Nonius Kappa CCD diffractometer. The structures were solved
using direct methods with SHELXS97. Non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were generated according
to stereochemistry and refined using a riding model in SHELXL97.
UV/Vis absorption spectra were recorded by using a Hitachi U-
3000 spectrophotometer. ICP-AES experiments were conducted at
the RepSem-ECPM laboratory, Strasbourg. CCDC 924923 contains
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data request/cif.
Synthesis of (S)–iPr-MeBnBox (2)
The general procedure was followed. 4.6 mmol, 58%; 1H NMR
(300 MHz, CDCl3): d=7.24–7.13 (m, 5H, Harom), 4.26–4.19 (m, 2H, À
NCH), 4.04–3.88 (m, 4H, ÀOCH2), 3.29 (q, 4J=13.5 Hz, 2H, ÀCH2),
1.83–1.68 (m, 2H, ÀCH(CH3)2), 1.42 (s, 3H, ÀC(CH3)), 0.92–0.79 ppm
(m, 12H, ÀCH(CH3)2); 13C{1H} NMR (300 MHz, CDCl3): d=167.6 (N=
CO), 136.7 (ÀCarom), 130.5 (ÀCarom), 127.9 (ÀCarom), 126.6 (ÀCarom), 71.9,
71.6 (ÀNCH), 70.1, 69.7 (ÀOCH2), 43.3 (ÀCCH3), 42.1 (ÀCH2), 32.5,
32.2 (ÀCH(CH3)2), 21.2 (ÀC(CH3)), 18.8, 18.7, 17.9, 17.4 ppm (À
CH(CH3)2); IR (KBr): n˜ =1659 cmÀ1 (s, C=N); MS (ESI+): m/z: 343.23
[M+H]+; elemental analysis calcd (%) for C21H30N2O2 (342.48): C
73.65, H 8.83, N 8.18; found C 73.43, H 8.72, N 7.95.
Synthesis of (R)–Ph-DiBox (4)
The general procedure was followed. 1.65 mmol (53% yield);
1H NMR (300 MHz, CDCl3): d=7.34–7.55 (m, 16H, Harom(PhBOX)), 7.17
(s, 4H, Harom), 7.12–7.09 (m, 4H, Harom(PhBOX)), 5.30–5.18 (m, 4H, À
NCH), 4.74–4.67 (m, 4H, ÀOCH2), 4.23–4.10 (m, 4H, ÀOCH2), 3.45 (s,
4H, ÀCH2), 1.64 ppm (s, 6H, ÀC(CH3)); 13C{1H} NMR (300 MHz,
CDCl3): d=169.3, 169.1 (N=CO), 142.3, 142.1, 135.1, 130.4, 128.7,
128.6, 128.5, 127.6, 127.5, 126.7 (ÀCarom), 75.33 (ÀNCH), 69.7, 69.6 (À
General Procedure for the enantioselective a-hydrazination
of b-ketoesters and recycling. Reaction of ethyl-2-methyl
acetoacetate (Table 2, Entry 1)
Cu(OTf)2 (2.2mg, 0.006mmol) and 4 (4.8mg, 0.0065mmol) were
added to a vial with methanol (1.0mL) under air. The mixture was
stirred for 2h and then dried in vacuo. Dichloromethane (1mL)
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OCH2), 43.8 (ÀCCH3), 41.8 (ÀCH2), 21.3 ppm (ÀC(CH3)); IR (KBr): n˜ =
1654 cmÀ1 (s, C=N); MS (ESI+): m/z: 765.34 [M+Na]+; elemental
analysis calcd (%) for C48H46N4O4 (706.96): C 77.60, H 6.24, N 7.54;
found C 77.90, H 6.30, N 7.23.
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[5] The formation of a charge-transfer complex also appears to be an inter-
esting approach for enantioselective catalyst recycling, see for example:
a) D. Dorian, C. Magnier-Bouvier, E. Schulz, Adv. Synth. Catal. 2011, 353,
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Synthesis of (S)–iPr-TriBox (5)
The general procedure was followed. 1.65 mmol (30% yield);
1H NMR (300 MHz, CDCl3): d=6.86 (s, 3H, Harom), 4.27–4.18 (m, 6H,
ÀNCH), 4.45–3.89 (m, 12H, ÀOCH2), 3.29–3.06 (m, 6H, ÀCH2), 1.81–
1.69 (m, 6H, ÀCH(CH3)2), 1.39 (s, 9H, ÀC(CH3), 0.93–0.81 ppm (m,
36H, ÀCH(CH3)2); 13C{1H} NMR (300 MHz, CDCl3): d=167.9, 167.3
(N=CO), 135.7 (ÀCarom), 131.3 (ÀCarom), 71.9, 71.6 (ÀNCH), 69.9, 69.6
(ÀOCH2), 43.3 (ÀCCH3), 41.9 (ÀCH2), 32.4, 32.2 (ÀCH(CH3)2), 21.3 (À
C(CH3), 18.6, 17.6, 17.4 ppm (ÀCH(CH3)2); IR (KBr): n˜ =1660 cmÀ1 (s,
C=N); MS (ESI+): m/z=871.60 [M]+; elemental analysis calcd (%)
for C51H78N6O6 (871.20): C 70.31, H 9.02, N 9.65; found C 69.94, H
9.13, N 9.38.
[8] J. I. Garcꢃa, C. I. Herrerꢃas, B. Lꢄpez-Sꢅnchez, J. A. Mayoral, O. Reiser, Adv.
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Synthesis of (S)–iPr-TetraBox (6)
[9] L. Aldea, I. Delso, M. Hager, M. Glos, J. I. Garcꢃa, J. A. Mayoral, O. Reiser,
Tetrahedron 2012, 68, 3417.
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The general procedure was followed. 0.15 mmol (171.1 mg, 38%).
1H NMR (300 MHz, CDCl3): d=6.95 (s, 2H, Harom), 4.29–4.18 (m, 8H,
ÀNCH), 4.04–3.67 (m, 16H, ÀOCH2), 1.73–1.66 (m, 8H, ÀCH(CH3)2),
1.29 (s, 12H, ÀC(CH3), 0.89–0.84 (m, 48H, ÀCH(CH3)2; 13C{1H} NMR
(300 MHz, CDCl3): d=167.7 (N=CO), 134.3 (ÀCarom), 133.3 (ÀCarom),
72.1, 71.5 (ÀNCH), 70.1, 69.6 (ÀOCH2), 43.9 (ÀCCH3), 37.2 (ÀCH2),
32.7, 32.2 (ÀCH(CH3)2), 20.8 (ÀC(CH3)), 18.9, 18.6, 18.0, 17.4 ppm (À
CH(CH3)2); IR (KBr): n˜ =1658 cmÀ1 (s, C=N); MS (ESI+): m/z: 1135.79
[M+H]+, 568.40 [M+HÀC33H51N4O4]+; elemental analysis calcd (%)
for C66H102N8O8 (1135.56): C 69.81, H 9.05, N 9.87; found C 69.49, H
9.06, N 9.21.
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Complex 7
Ligand 6 (42 mg, 0.04 mmol) dissolved in dichloromethane (3 mL)
was added to CuCl2 (21.5 mg, 0.16 mmol), and the resulting green
solution was stirred overnight. The diffusion of methanol/cyclohex-
ane into this solution by vapor diffusion led to crystals suitable for
X-ray diffraction. IR (KBr): n˜ =1650 cmÀ1 (s, C=N); elemental analysis
calcd (%) for C66H102Cl8Cu4N8O8·2(CH3OH) (1673.37): C 47.01, H 6.38,
N 6.45; found C 47.48, H 6.54, N 6.21. Crystal data for 7:
C66H102Cl8Cu4N8O8·3(CH4O);
15.5526(4), b=18.3310(7), c=16.4599(5) ꢂ; a=90, b=90.400(2),
g=908; V=4692.5(3) ꢂ3; T=173(2) K; space group P21; Z=2; Data
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Mw =1769.44;
monoclinic;
a=
[16] For our previous investigations, see : a) M. Gaab, S. Bellemin-Laponnaz,
L. H. Gade, Chem. Eur. J. 2009, 15, 5450; b) L. H. Gade, S. Bellemin-La-
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completeness=1.67/0.86; qmax =27.480;
(15137); wR2 (reflections)=0.2410 (18578).
R (reflections)=0.0951
[17] 4 mol% of Cu salt was used for the catalytic studies. The ligand-to-Cu
ratio was adapted for each polytopic ligand for the formation of the co-
ordination polymer, that is, 1:1 for 3 and 4, 0.66:1 for 5, and 0.5:1 for
6.
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Acknowledgements
The authors gratefully acknowledge the CNRS and the Ministꢁre
de l’Enseignement Supꢀrieur et de la Recherche (MESR) for a PhD
grant to M.T. The authors also thank Dr. C. Bailly and Dr. L.
Brelot for performing the X-ray diffraction studies (Strasbourg).
We thank Samuel Dagorne for critical reading of the manuscript.
[19] See for example : a) I. Welterlich, B. Tieke, Macromolecules 2011, 44,
4194; b) D. Knapton, S. J. Rowan, C. Weder, Macromolecules 2006, 39,
651; c) A. Winter, C. Friebe, M. Chiper, M. D. Hager, U. S. Schubert, J.
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Catal. 2001, 343, 227; c) H. B. Kagan, Oil Gas Sci. Technol. 2007, 62, 731.
Keywords: copper
catalysis · ligand design · ligand effects
·
enantioselectivity
·
homogeneous
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FULL PAPERS
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Received: May 23, 2013
Published online on August 15, 2013
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2013, 5, 3078 – 3085 3085