Original use of the same heterogeneous chiral catalyst batch to promote different asymmetric reactions

Article abstract of DOI:10.1039/b913516b

An electrogenerated heterogeneous chiral (poly)salen-thiophene chromium complex successfully promoted different asymmetric catalytic reactions in an original successive manner, demonstrating its high stability and versatility. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b913516b

Chemical Communications
www.rsc.org/chemcomm
Number 43 | 21 November 2009 | Pages 6497–6668
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ISSN 1359-7345
FEATURE ARTICLE
Gregory L. Challis et al.
The long-overlooked enzymology of
COMMUNICATION
Emmanuelle Schulz et al.
Original use of the same heterogeneous a nonribosomal peptide synthetase-
chiral catalyst batch to promote
different asymmetric reactions
independent pathway for virulence-
conferring siderophore biosynthesis

COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Original use of the same heterogeneous chiral catalyst batch to promote
different asymmetric reactionsw
Anaıs Zulauf, Mohamed Mellah and Emmanuelle Schulz*
¨
Received (in Cambridge, UK) 8th July 2009, Accepted 28th August 2009
First published as an Advance Article on the web 14th September 2009
DOI: 10.1039/b913516b
An electrogenerated heterogeneous chiral (poly)salen-thiophene
chromium complex successfully promoted different asymmetric
catalytic reactions in an original successive manner, demonstrating
its high stability and versatility.
during the recycling procedures, showing a stable efficiency in
both their activity and enantioselectivity. Such complexes,
immobilized in a continuous flow reactor, should be very
useful in an economical industrial procedure for the preparation
of structurally diverse enantioenriched compounds from the
same reactor with the same catalyst.
Asymmetric catalysis has gained special attention from
organic chemists as a more straightforward, economic and
safe way to produce valuable enantioenriched synthons. Some
optimized procedures have also already been developed at the
To the best of our knowledge, such a procedure with
asymmetric catalysts has very rarely been described in the
literature. One recent example was described by Mayoral’s
10
1
industrial scale, proving the feasibility of such developments,
group,
in which heterogeneous copper complexes of
especially in the field of enantioselective hydrogenation
reactions. However, some important efforts are still needed
to generally improve these methods, since organometallic
catalysts are often composed from both precious and costly
metals and ligands. Even if they are usually used in a small
quantity, their efficient recovery and reuse is nowadays
essential to propose competitive processes. A lot of academic
work has been devoted to the fine tuning of asymmetric
catalysis under specific conditions, including biphasic systems,
heterogeneous reactions, precipitation procedures, etc. that
allow the recovery and reuse of the valuable organometallic
chiral complexes. Such efforts have been completed with
azabis(oxazolines) were able to promote a Mukaiyama and
subsequently cyclopropanation reaction, showing
a
a
multipurpose character. We have chosen to demonstrate this
concept by using salen-based complexes that have already
repeatedly proven their ability to powerfully promote
1
1
numerous asymmetric transformations.
Among them,
chromium derivatives were shown to catalyze various
1
carbon-carbon or carbon-heteroatom reactions.
2
1
3
We have previously reported an efficient procedure for
the preparation of heterogeneous chiral chromium-salen
complexes involving the electrochemical polymerization of
targeted thiophene-salen monomers (Scheme 1).
2
the most popular ligands including, for example, BINAP,
The monomers were prepared through a Suzuki-coupling
between boronic derivatives of thiophene and 5-bromo-3-tert-
3
4
bis(oxazoline) derivatives and also salen-type ligands. Some
important examples can be found in which these ligands,
when associated to various metals, allowed the production of
enantioenriched synthons with overall very high global
turnover in repetitive batch procedures, or even in continuous
butyl-2-hydroxybenzaldehyde, followed by
a subsequent
condensation reaction with (S,S)-cyclohexane-1,2-diamine.
The insertion of the chromium salt occurred according to
1
4
known procedures and led, for example, to the formation of
cat-1 with very high yield. The corresponding insoluble chiral
polymer (poly)cat-1 was obtained in 43% yield by anodic
polymerization at a constant current of 50 mA. We have
described the efficient use of each new complex, either as a
homogeneous catalyst or as a heterogeneous promoter, in
two asymmetric transformations involving various aldehydes
as substrates, i.e. the hetero-Diels–Alder reaction with
Danishefsky’s diene and the Henry reaction with nitro-
methane. The results obtained with both of the catalysts
5
flow reactors. Far fewer procedures describe reuse of the same
catalyst batch for the transformation of substrates possessing
6
different structures during the recycling procedure.
Recently, we successfully described such a concept by using
7 8,9
bis(oxazoline) derivatives, but also chromium-salen catalysts,
as a proof for the high stability of these asymmetric complexes
and the feasibility of this procedure. The targeted compounds
were obtained each time without contamination of any traces
of molecules from the preceding run. This demonstrates the
usefulness of such reusable catalysts for preparing structurally
diverse valuable synthons with the same promoter batch in a
highly economical procedure.
represented in Scheme
1
are summarized in Table
1
1
4–16
entries 1–4. The hetero-Diels–Alder
reaction was equally
well catalyzed with the soluble catalyst cat-1 as it was with
its insoluble counterpart (poly)cat-1 in terms of activity.
In a subsequent step, we wondered if such elaborated
complexes could promote different asymmetric transformations
Equipe de Catalyse Mole´culaire, ICMMO, UMR CNRS 8182,
Universite´ Paris-Sud 11, 91405 Orsay cedex, France.
E-mail: emmaschulz@icmo.u-psud.fr; Fax: 00 33 (0) 169154680
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization and ee determinations. See DOI:
1
0.1039/b913516b
Scheme 1 Synthesis of chiral thiophene-salen catalysts.
This journal is ꢀc The Royal Society of Chemistry 2009
6
574 | Chem. Commun., 2009, 6574–6576

Table
complexes as chiral catalysts
1
Monomeric and polymeric chromium thiophene-salen
dramatic decrease in the enantioselectivity value was observed
when comparing the homogeneous and the heterogeneous
catalysts (compare entries 5–6 in Table 1) since (poly)cat-1
delivered compound 6 in its nearly racemic form. An explana-
tion for such results is probably to be found in the mechanistic
pathway proposed to account for the ring-opening of
a
b
Entry
Catalyst
Yield (%)
ee (%)
1
9
epoxides. Indeed, a bimolecular mechanism is now stated
involving two catalytic species in a cooperative way to activate
both the epoxide ring and the nucleophile. One may imagine
that the arrangement of the catalytic sites in the electro-
generated (poly)salen-thiophene chromium complex in a pearl
necklace manner is not favorable for this specified optimized
position of the catalytic sites.
1
2
cat-1
(poly)cat-1
53
63
72
63
3
4
cat-1
(poly)cat-1
88
92
74
54
Finally, the recent transformation described by Cozzi
2
0
and Kotusz consisting of the addition of dimethylzinc to
aldehydes has been tested under our conditions. These authors
indeed developed a highly enantioselective addition of the
5
6
cat-1
(poly)cat-1
98
75
49
3
2
low reactive Me Zn to benzaldehyde catalyzed by the
commercially available chiral Jacobsen salen-chromium
chloride complex. Accordingly, we were delighted to notice
that cat-1 promoted this transformation with an excellent
efficiency and with up to 93% ee (see Table 1, entry 7). The
corresponding polymeric complex was introduced as the
catalyst in this transformation and was, surprisingly, almost
inactive for the synthesis of compound 8. Such a different
behaviour in terms of activity between our homogeneous
catalyst and its heterogeneous counterpart was not observed
in the other transformations and still remains to be questioned.
As Cozzi invoked a possible mechanism involving activation
of the carbonyl group and/or activation of the alkylating agent
by the chromium catalytic center, one may only imagine that
the restricted flexibility of the salen centers in the insoluble
polymer is totally detrimental to promotion of the catalytic
reaction.
7
8
cat-1
(poly)cat-1
79
5
93
20
a
b
Isolated yield. Enantiomeric excesses were determined by chiral
GC or HPLC analyses (see the ESI).w
Interestingly, this transformation is thus not restricted by
potential mass transfer limitations. 2-Hexyl-2,3-dihydropyran-
4
-one (2) was obtained with enantioselectivities reaching 72%,
with a slight decrease of the value by using (poly)cat-1
8
see entries 1–2 in Table 1). Both catalysts also proved their
(
efficiency for the preparation of nitroalcohol adducts via the
1
7
Henry reaction, as summarized in Table 1, entries 3–4. Here
again, 1-(2-methoxyphenyl)-2-nitroethanol (4) was synthesized
with satisfying yields in both homogeneous and heterogeneous
procedures; however, use of the insoluble polymer as the
catalyst led to a diminished enantioselectivity value compared
Our insoluble polymeric catalyst could be easily separated
from the reaction products each time by a simple filtration.
Because we have examined four different transformations, we
also performed these transformations successively with the
same catalyst batch, which was recovered after each reaction
and directly reused in the next one.
9
to its homogeneous analogue.
As chromium-salen complexes reported by Jacobsen
demonstrated their high ability to promote the asymmetric
The results obtained by testing this new original procedure
using (poly)cat-1 are summarized in Table 2. The first reaction
we attempted was the addition of dimethylzinc to benzalde-
hyde for the preparation of phenylethanol (8). Although this
transformation was not successfully performed with (poly)cat-1
(see Table 1), our multireaction procedure could give
important information on a possible structure modification
of the polymeric catalyst after its use under those reaction
conditions. Thus, and as expected, the first catalytic run led to
the production of compound 8 in a very low yield and
enantiomeric excess. Gratifyingly however, the recovered
polymer was efficiently used in a second run to catalyze the
hetero-Diels–Alder reaction with an effectiveness analogous,
in terms of activity and enantioselectivity, to that obtained
with a new catalytic set (compare Table 2, 2nd run, with
Table 1, entry 2). This result is fundamental to prove
the integrity of the catalyst after being subjected to the
dimethylzinc addition reaction conditions. The catalytic batch
was then subjected to the Henry reaction in a third run, and
1
8
opening of epoxides by nucleophiles, we wondered whether
our new catalysts could also be promoters in such transforma-
tions. We considered the test reaction of the nucleophilic
addition of trimethylsilylazide to cyclohexene epoxide in
MTBE at room temperature. The transformation was first
performed under homogeneous conditions in the presence of
the soluble catalyst cat-1 (see Table 1, entry 5). Quite long
reaction times (3 d) were necessary to ensure complete
conversion of the substrate, and the product was isolated with
an excellent yield. However, (2-azidocyclohexyloxy)trimethyl-
silane (6) was obtained with only 49% ee by using cat-1 as the
catalyst, a much lower value compared to that obtained in
the presence of Jacobsen’s catalyst under similar conditions
1
8
(
i.e. 88% ee).
The corresponding polymeric complex was also proven to
efficiently promote this transformation since the targeted
product 6 was isolated in high yield after a reaction time of
3
d (see Table 1, entry 6). However, for this transformation, a
This journal is ꢀc The Royal Society of Chemistry 2009
Chem. Commun., 2009, 6574–6576 | 6575

Table 2 Same batch of (poly)cat-1 as a catalyst for promoting
different asymmetric reactions
The CNRS, the Ministe
`
re de l’Enseignement Supe
´
rieur et de
la Recherche and the program ‘‘Chimie et De
´
veloppement
a
b
c
Durables’’ du CNRS are acknowledged for financial support.
Entry
Products
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
st run
nd run
rd run
8
2
4
6
8
2
4
6
2
20
93
86
85
9
66
94
79
64
24
63
51
3
Notes and references
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d
th run
th run
th run
th run
th run
th run
6
65
29
3
d
64
J. M. Fraile, J. I. Garcı
008, 252, 624; J. M. Fraile, J. I. Garcı
J. A. Mayoral, E. Pires and L. Salvatella, Catal. Today, 2009,
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5 W. Solodenko, G. Jas, U. Kunz and A. Kirschning, Synthesis,
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S. E. Schaus, J. F. Larrow and E. N. Jacobsen, J. Org. Chem.,
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´
a and J. A. Mayoral, Coord. Chem. Rev.,
2
´
a, C. I. Herrerıas,
´
a
10 mol% of catalyst compared to benzaldehyde was initially
introduced. The reactions were performed at room temperature for
1
b
3 h. Isolated yield. Enantiomeric excesses were determined by
c
2
˜
o and H. Garcia, Chem. Rev., 2006, 106, 3987.
d
chiral GC or HPLC analyses (see the ESI).w Reaction time = 72 h.
2
6
again the results are totally similar to those reported in
Table 1, entry 4. Finally, the last transformation, the nucleo-
philic opening of cyclohexene oxide (5), was performed in the
next run leading to the same activity and enantioselectivity as
those described before (Table 2, 4th run and Table 1, entry 6).
The exceptional stability of (poly)cat-1 under different reaction
conditions was fully proven by involving the same batch again
in four new runs (Table 2, 5th–8th runs) with the same
successive series of transformations.
1
´
´
J. A. Mayoral, O. Reiser and M. Vaultier, Tetrahedron Lett.,
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7
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1
3, 992.
Each run is comparable to the one from the preceding
sequence, except for the nitroaldol reaction which led to less
reproducible results in terms of enantioselectivity. The last use
of the catalyst batch, initially introduced in a 10 mol%
quantity, the 8th reuse of the polymer, was a hetero-Diels–
Alder reaction, delivering compound 8 with the expected 64%
ee in a satisfying yield. After each transformation, the
recovered crude mixtures were examined by NMR spectro-
scopy, giving spectra in all points identical to those that arose
from using new catalyst batches and the expected compounds
were isolated in their pure form.
8 A. Zulauf, M. Mellah, R. Guillot and E. Schulz, Eur. J. Org.
Chem., 2008, 2118.
9
A. Zulauf, M. Mellah and E. Schulz, J. Org. Chem., 2009, 74, 2242.
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´
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1
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As far as we know, this recycling procedure is the first
example for which the same catalyst batch is involved in
multi-reaction procedures to synthesize enantioenriched
compounds. Although the selectivities are not high, they
exactly match those obtained under classical heterogeneous
catalysis. The reproducibility of these results is clear proof of
the high stability and versatility of our electrogenerated chiral
1
7 R. Kowalczyk, Ł. Sidorowicz and J. Skar z˙ ewski, Tetrahedron:
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(
poly)salen-thiophene chromium complex.
6
576 | Chem. Commun., 2009, 6574–6576
This journal is ꢀc The Royal Society of Chemistry 2009