Highly enantioselective aza-Baylis-Hillman reaction in a chiral reaction medium

Article abstract of DOI:10.1002/anie.200600327

Let's twist again! The first highly enantioselective asymmetric reaction in which a chiral reaction medium is the sole source of chirality is presented. The aza-Baylis-Hillman reaction in an ionic liquid with a chiral anion, whose design is based on mecha

Full text of DOI:10.1002/anie.200600327

Angewandte
Chemie
Chiral Solvents
DOI: 10.1002/anie.200600327
Highly Enantioselective Aza-Baylis–Hillman
Reaction in a Chiral Reaction Medium**
Rolf Gausepohl, Pascal Buskens, Jochen Kleinen,
Angelika Bruckmann, Christian W. Lehmann,
Jürgen Klankermayer, andWalter Leitner*
Dedicated to Professor Dieter Enders
on the occasion of his 60th birthday
A chemical reaction that leads to enantiomerically enriched
products can in principle be carried out with a source of
chirality in any of the involved components—starting materi-
[*] R. Gausepohl, P. Buskens, J. Kleinen, A. Bruckmann,
Dr. J. Klankermayer, Prof. Dr. W. Leitner
Institut für Technische und Makromolekulare Chemie
Rheinisch-Westfälische Technische Hochschule Aachen
Worringerweg 1, 52074 Aachen (Germany)
Fax: (+49)241-80-22177
E-mail: leitner@itmc.rwth-aachen.de
Dr. C. W. Lehmann, Prof. Dr. W. Leitner
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1
45470 Mülheim an der Ruhr (Germany)
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(SPP 1179, SFB 380). R.G. and P.B. thank the Fonds der Chem-
ischen Industrie and the Graduate School 440 “Methods in
Asymmetric Synthesis”, respectively, for PhD stipends. We thank Dr.
K. Ditrich (BASF AG) for a generous gift of (R)-mandelic acid.
Furthermore, we are very grateful to H. Eschmann and T. Steins for
their technical support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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als,[1] catalysts,[2] or reaction media.[3] To date, all asymmetric metric reaction.[10a] In the DABCO-catalyzed Baylis–Hillman
transformations that yield appreciable enantioselectivities are
reaction (DABCO = 1,4-diazabicyclo[2.2.2]octane) of benzal-
dehyde and methylacrylate they obtained enantioselectivities
up to 44% ee (e.r. = 2.6) by using an IL with chiral cations
derived from (À)-N-methylephedrine. To the best of our
knowledge, no significant asymmetric induction has been
reported so far for ILs with chiral anions.
Previous investigations on the mechanism of the aza-
Baylis–Hillman reaction by our group indicate that a bifunc-
tional stabilization of the zwitterionic reaction intermediates
is necessary to obtain high enantioselectivities and to prevent
subsequent racemization of the reaction product 4.[11] In
conventional systems, this can be achieved by incorporating
both a nucleophilic catalyst and a Brønsted acidic co-catalyst
into one chiral molecule. ILs, however, offer the possibility of
establishing a bifunctional interaction by incorporating the
acidic center into the chiral anion of the solvent, thus allowing
monofunctional achiral nucleophiles to be used as catalysts in
the enantioselective aza-Baylis–Hillman reaction (Figure 1).
based on the first two strategies. Herein we report the first
example of a highly enantioselective asymmetric synthesis in
which only the reaction medium contains chiral information.
We focused our investigations on the aza-Baylis–Hillman
À
reaction, a C C-bond forming reaction of activated alkenes
(e.g., 2) with imines (e.g., 1).[4] This organocatalytic trans-
formation is catalyzed by nucleophilic Lewis bases such as
tertiary phosphines (3) and leads to highly functionalized
chiral allylic amines (4) (Scheme 1). The previously devel-
Scheme 1. The aza-Baylis–Hillman reaction. Tos=4-toluenesulfonyl.
oped methods for enantioselective synthesis of the allylic
amine 4 provide the necessary chiral information within the
substrate[5] or through catalysts.[6] We have prepared the ionic
liquid (IL) 9, which contains a chiral anion and induces high
enantioselectivities (up to 84% ee) when used as reaction
medium.
Figure 1. Possible bifunctional interaction of the zwitterionic intermedi-
ate of the aza-Baylis–Hillman reaction with the chiral anion of an IL
containing a hydrogen-bond donor.
The strategy of applying chiral solvents in asymmetric
synthesis was pioneered by Seebach and Oei.[7] They used a
chiral amino ether as the solvent in the electrochemical
reduction of ketones but observed only low enantioselectiv-
ities (up to 23.5% ee). Since then, all attempts to apply chiral
solvents in asymmetric synthesis
For ions containing hydrogen-bond donor functions, we
targeted borate anions based on l-(À)-malic acid, which is
available from the chiral pool (Scheme 2). The sodium
dimalatoborate salt 8 was prepared by stirring an aqueous
have resulted in similar or lower
enantioselectivities. This led to
the generally accepted conclu-
sion that “asymmetric induction
caused by chiral solvents is usu-
ally rather small”.[3]
As ILs have attracted a lot of
attention recently as a new class
of solvents,[8] the incorporation of
chiral information in these media
has caught the interest of several
groups.[9] Although details of the
structure and dynamics of these
solvents as well their interactions
with dissolved substances remain
largely elusive, chiral ILs have
already started to emerge for
various purposes[9] including
asymmetric synthesis.[10] Very
recently, Vo-Thanh and co-work-
ers reported the largest presently
known asymmetric induction
caused by a chiral IL as the only
source of chirality in an asym-
Scheme 2. Two-step synthesis of methyltrioctylammonium dimalatoborate (9). Only one of the two
possible diastereoisomers is shown.
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solution of boric acid (5), sodium hydroxide (6), and l-(À)-
malic acid (7) in an open flask at 1008C.[12] Figure 2 depicts
the molecular structure of the anion as revealed by X-ray
crystal structure analysis,[13] which proves the connectivity and
Several experiments were carried out to investigate the
mechanism of the chirality transfer by the chiral reaction
medium.[17] Notably, the structurally related ILs 10 and 11
resulted in lower conversions (15% and 14%, respectively)
and the formation of racemic product, which indicates the
necessity of a Brønsted acidic moiety within the chiral ion.[11]
Dilution experiments with one equivalent of 9, 8, or 7 per
molecule of 3 in THF or CH2Cl2 also resulted only in the
formation of small amounts of racemic product. These results
show that neither 9 nor any of its chiral precursors can be used
as an additive for the asymmetric aza-Baylis–Hillman reac-
tion in conventional solvents. Consequently, the use of 9 as a
reaction medium is crucial for effective asymmetric trans-
formation in this system.
Almost identical results were obtained with substrate 1a
using other aryl phosphines (3) as the achiral nucleophilic
catalyst in 9 as the reaction medium (P(o-tolyl)3: 35%
conversion, 74% ee (R); (C6F5)PPh2: 9% conversion,
71% ee (R)). The catalyst PPh3 also led to reasonable
conversion (39%) and a high level of enantioselectivity
(64% ee) for the p-methyl-substituted substrate 1b. With the
less electron-rich substrate 1c, however, product 4c was
obtained in only 10% ee. A control experiment showed that
this results from a lower level of intrinsic asymmetric
induction, as no racemization of 4c occurred under turnover
conditions. A similar decrease in asymmetric induction was
described by Vo-Thanh and co-workers for the mechanisti-
cally related Baylis–Hillman reaction of p-nitrobenzaldehyde
Figure 2. Molecular structure of the dimalatoborate anion in the solid
state as revealed by X-ray single-crystal structure analysis of the
corresponding sodium salt 8. Only the S,S,S diastereoisomer is
present in the crystal lattice. The O-B-O angles range from 103.9 to
105.18 within the five-membered ring and from 109.0 to 113.48
between the rings (see the Supporting Information for details).
configuration indicated in Scheme 2. Multinuclear NMR
experiments confirmed the presence of the five-membered
ring arrangement also in solution. Two sets of signals are and methylacrylate in ILs with chiral ephedrinium cations.[10a]
1
observed in a 1:1 ratio in the H and 13C NMR spectra of
samples of dissolved single crystals even at low temperature
(233 K, [D4]MeOH). This is due to the formation of a 1:1
mixture of the two possible diastereoisomers that result from
the fixed chirality at the asymmetric carbon atoms and the
labile chirality at the boron center of this spiro-type com-
pound.[14]
They explained the drop in enantioselectivity by the forma-
tion of a hydrogen bond between the OH group of the chiral
ion and the NO2 function of the substrate.
In conclusion, we reported the first example of an
asymmetric reaction in which a chiral reaction medium
induces a high level of enantioselectivity. Using a specifically
designed ionic liquid with a chiral anion as the only source of
chirality, enantioselectivities of up to 84% ee (DDG° =
6.05 kJmolÀ1) were obtained in the aza-Baylis–Hillman
reaction. This is the highest enantioselectivity induced to
date by a solvent as the sole source of chirality. These results
are comparable with the values obtained with the best
catalysts for the asymmetric aza-Baylis–Hillman reaction in
conventional solvents (94% ee,[6e] 83% ee[6c,d]).
The exchange of the sodium ions with methyltrioctylam-
monium (MtOA) was carried out with aliquat 336 (MtOACl)
in acetone. Filtration of the precipitated NaCl and evapo-
ration of the solvent yielded a colorless liquid with a melting
point of À328C.[15] The related ILs 10 and 11, which lack a
potential hydrogen-bond donor, were prepared in a similar
manner.
To assess the efficacy of the IL 9 for chiral induction, the
aza-Baylis–Hillman reaction between methyl vinyl ketone (2)
and N-(4-bromobenzylidene)-4-toluenesulfonamide (1a) was
studied in the new reaction medium using PPh3 (3, R = Ph) as
the nucleophilic catalyst (see Experimental Section). The
chiral allylic amine (R)-4a was obtained in this model
reaction with reasonable conversion and high enantiomeric
excess.[16] In a series of four independent experiments using
various batches of 9, conversion varied between 34% and
The results described herein demonstrate that, contrary to
popular opinion, the strategy of applying chiral solvents in
asymmetric synthesis can result in appreciable enantioselec-
tivities. The key to effective chirality transfer lies in strong
intermolecular interactions such as electrostatic attraction
and hydrogen bonding between the solvent molecules and the
intermediates or transition states of the enantioselective
reaction step (see Figure 1). Functional ionic liquids offer
unique possibilities to create such arrangements for a wide
39% and the enantioselectivity ranged from 71–84% ee. T he range of transformations.
highest enantiomeric excess (84% ee) observed in these
experiments corresponds to an enantiomeric ratio of 11.5
and hence a difference in activation energies DDG° of
Experimental Section
8: 7 (10.73 g, 80.0 mmol, 2.00 equiv) was dissolved in water (10 mL)
6.05 kJmolÀ1 for the formation of the two enantiomers. This is
by far the highest asymmetric induction obtained with a chiral
solvent as the sole source of chirality.
and treated with boric acid (5, 2.47 g, 40.0 mmol, 1.00 equiv). A
solution of sodium hydroxide (6, 1.60 g, 40.0 mmol, 1.00 equiv) in
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Communications
water (30 mL) was then added. The reaction mixture was stirred in an
Wang, Q. Wang, Y. Zhang, W. Bao, Tetrahedron Lett. 2005, 46,
4657 – 4660.
[11] P. Buskens, J. Klankermayer, W. Leitner, J. Am. Chem. Soc. 2005,
127, 16762 – 16763.
[12] The corresponding Li salt: P. H. Cunningham, F. L. Warren, Jr.,
H. O. Marcy, M. J. Rosker (Rockwell International Corp.,
USA), EP-95-109113 693704, 1996.
open flask at 1008C. After evaporation of the water (ca. 4 h), 8 was
isolated as a white powder (11.92 g; 40.0 mmol, > 99% yield).
9: Methyltrioctylammonium chloride (3.54 g, 8.75 mmol,
1.00 equiv) was dissolved in acetone (20 mL) and treated with a
solution of the sodium borate salt 8 (2.61 g, 8.75 mmol, 1.00 equiv) in
acetone (20 mL). The reaction mixture was stirred at room temper-
ature overnight. During this period, sodium chloride precipitated as a
white solid. The reaction mixture was filtered and the solvent was
removed in vacuo to yield 9 as a highly viscous, hygroscopic colorless
liquid.
Typical procedure for the aza-Baylis–Hillman reaction:4a: Imine
1a (0.125 mmol, 1.00 equiv) and catalyst 3 (12.5 mmol, 0.10 equiv)
were dissolved in 9 (1.0 mL, 6.7 mL per mmol 1). After addition of 2
(12.5 mL, 10.5 mg, 0.150 mmol, 1.20 equiv), the reaction was stirred at
room temperature for 24 h. Excess 2 was removed in vacuo, a small
sample of the reaction mixture was dissolved in [D6]DMSO, and the
conversion was determined by 1H NMR spectroscopy. The rest of the
reaction mixture was dissolved in water/methanol (1:1, 5 mL).
Further methanol was added to obtain a clear solution of the reaction
mixture. After (partly) exchanging the cation on an ion-exchange
resin (contact time approximately 5 min), all volatile substances were
removed in vacuo. The resulting solid was extracted with heptane/
iPrOH (85:15, 1 mL), and the solution was directly analyzed by
HPLC on a chiral phase to determine the enantiomeric excess of 4a.
[13] Crystal data for 8: C8H8BNaO10, Mr = 297.9, crystal dimensions
0.36 ” 0.34 ” 0.25 mm3, monoclinic P21 (No. 4), T= 100 K a =
5.40160(10), b = 11.6781(2), c = 9.4451(2) Š, b = 105.0590(10),
V= 575.340(19) Š3, 1calcd = 1.720 MgmÀ3, CuKa radiation, l =
1.54178 Š. CCD scans yielded 10760 (1906 unique) reflections,
R
T
int = 0.038. Multi-scan absorption correction, m = 1.719 mmÀ1
min = 0.85, max = 1.0. Structure solution (direct methods)
,
T
SHELXS-97, full-matrix least-squares refinement against F2
SHELXL-97, 213 parameters, hydrogen atoms in idealized
geometry (riding model) R = 0.025, wR = 0.077, highest residual
electron density peak 0.2 ŠÀ3. Complete lists of atom coordi-
nates and anisotropic displacement parameters as well as tables
of bond lengths and bond angles are available as supplementary
material. CCDC-297143 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[14] a) J. Boeseken, J. A. Mijs, Recl. Trav. Chim. Pays-Bas 1925, 44,
758 – 762; b) S. Green, A. Nelson, S. Warriner, B. Whittaker, J.
Chem. Soc. Perkin Trans. 1 2000, 4403 – 4408; c) J. Lacour, V.
Hebbe-Viton, Chem. Soc. Rev. 2003, 32, 373 – 382.
Received: January 25, 2006
Revised: March 10, 2006
[15] The melting point was determined by differential scanning
calorimetry; 72 Æ 2% conversion (determined from 1H NMR
spectroscopy); impurities: octanol (from aliquat 336, up to 6%),
water (200–2800 ppm, determined by Karl Fischer titration).
[16] The absolute configuration of 4a–c was assigned as R by
comparison with the work of Shi et al.[6d]
[17] The possibility of enrichment of one enantiomer during workup
was excluded by subjecting a scalemic mixture of 4c to the same
experimental procedure. This control material had 74% ee (S)
before and 76% ee (S) after the workup procedure.
Keywords: asymmetric synthesis · C–C coupling ·
chiral solvents · ionic liquids · organocatalysis
.
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