Silylated pyrrolidines as catalysts for asymmetric Michael additions of aldehydes to nitroolefins

Article abstract of DOI:10.1002/chem.201001764

Silicon can! A convenient synthesis of enantiopure (S)-2- (diphenylmethylsilyl)pyrrolidine is described and its organocatalytic activity in asymmetric Michael reactions is demonstrated (see scheme). By using 10 mol% of this novel organocatalyst, the addition of aldehydes to nitroolefins affords products with high stereoselectivities (d.r. 97:3 and e.r. 95:5) in yields up to 99%.

Full text of DOI:10.1002/chem.201001764

COMMUNICATION
DOI: 10.1002/chem.201001764
Silylated Pyrrolidines as Catalysts for Asymmetric Michael Additions
of Aldehydes to Nitroolefins
Ralph Husmann, Manuel Jçrres, Gerhard Raabe, and Carsten Bolm*[a]
Silicon-containing compounds play an important role in
organic chemistry. In the field of organocatalysis the incor-
poration of silyl groups allows steric and electronic modifi-
cations, which lead to catalytic systems with improved prop-
erties.[1] The first example of 4-siloxyproline reported by
Hayashi et al.[2] and, in particular, the introduction of silylat-
ed l-prolinol derivatives I, simultaneously developed by the
groups of Hayashi and Jørgensen,[3] were major break-
throughs in this field.[4] It is noteworthy that in these cata-
lysts, silicon is always bound through an oxygen atom, thus
acting as a sterically demanding protecting group of a hy-
droxyl function. Many other rationally designed organocata-
lysts have been described since the pioneering work by the
groups of List and MacMillan.[4–6] Herein, we present the
synthesis of enantiopure 2-silylated pyrrolidines II and the
application of such compounds as asymmetric organocata-
lysts.
gen atom of the heterocyclic core could be an effective orga-
nocatalyst. The stabilization of a positive charge in the vicin-
ity of the silicon atom[11] is a key factor, and its use in asym-
metric organocatalysis conceptually new. In this scenario
(Scheme 1), iminium-type structure B is formed from cata-
Scheme 1. Proposed mechanism for a 2-silylated pyrrolidine catalyzed
Michael addition.
Our group has focused on the synthesis of a-silyl-a-amino
acids[7] and related silicon-containing compounds.[8] In this
context it was shown that a-silylated a-hydroxyacetic acids
were effective as chiral ligands in aldol-type reactions.[8a]
These findings and a thorough analysis of the widely accept-
ed mechanism of the 1,4-conjugate addition of enamine nu-
cleophiles[9,10] led us to hypothesize that a pyrrolidine with a
silicon group directly attached in the a position to the nitro-
lyst A and the reacting aldehyde. The silicon effects could
facilitate this initial, crucial step and thereby promote the
catalytic cycle. Enamine C is formed from intermediate B.
Also in this step the silicon group is key, because its bulk af-
fects the preferential formation of the E diastereomer. Sub-
À
sequently, a new C C bond is formed by the addition of C
to the unsaturated electrophile, for example, a nitroolefin.
Here, the silicon supports the substrate orientation and pro-
vides the basis for the enantioselective coupling. Finally, the
product is released and the catalyst liberated.
[a] R. Husmann, M. Jçrres, Prof. Dr. G. Raabe, Prof. Dr. C. Bolm
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52056 Aachen (Germany)
The synthesis of trimethylsilylated N-tert-butyloxycarbon-
yl (N-Boc)-protected pyrrolidines by asymmetric deprotona-
tion of N-Boc-pyrrolidine was first described by Beak et al.
and further investigated independently by the groups of
OꢀBrien and Coldham.[12] Their optimized procedure was
employed here for the preparation of silylated N-Boc-pyrro-
Fax : (+49)241-8092-391
E-mail: carsten.bolm@oc.rwth-aachen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001764.
Chem. Eur. J. 2010, 16, 12549 – 12552
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12549

lidines 1a–d (Scheme 2).[13] In accordance with the litera-
ture, products 1a and 1b were obtained with high enantiose-
lectivities in good yields.[12] Along the same lines, N-Boc-2-
Figure 1. Crystal structure of (S)-2-(diphenylmethylsilyl)pyrrolidine HCl
salt (2c).[16] Ellipsoids at the 50% level.
The best overall result was achieved in a Michael addition
reaction of propanal to trans-4-methyl-b-nitrostyrene, which
afforded product 6g with a syn/anti ratio of 96:4, an e.r. (for
the syn diastereomer) of 95:5 in a yield of 98% (Table 1,
entry 7).
Scheme 2. Synthesis of enantiopure (S)-2-(diphenylmethylsilyl)pyrroli-
dine (3).
(diphenylmethylsilyl)pyrrolidine (1c) was formed with an
enantiomeric ratio (e.r.) of 98:2 in 93% yield. Unexpectedly,
silylation with triphenylsilyl chloride gave the corresponding
product 1d only in moderate yield and, furthermore, prod-
uct 1d was almost racemic. Deprotection of 1a–c was effect-
ed with hydrochloric acid to give the hydrochloric salts 2a–
c. Whereas (S)-2-(trimethylsilyl)pyrrolidine HCl salt (2a)
was obtained in low yield, compounds 2b and 2c were iso-
lated in 90% and quantitative yield, respectively. Recrystal-
lization of 2c from a mixture of CH2Cl2/MeOH afforded the
enantiopure HCl salt of (S)-2-(diphenylmethylsilyl)pyrroli-
dine (2c) in 90% yield. The e.r. values were determined by
HPLC analysis after converting the HCl salts 2a–c into their
benzoyl-protected derivatives.[14] Finally, treatment of 2c
with base afforded the free amine 3 in quantitative yield.
The absolute configuration of (S)-2c was determined by
In conclusion, a conceptually new type of chiral organoca-
talyst has been found, and its applicability in asymmetric
Michael-type addition reactions has been demonstrated.
This initial study was performed with (S)-2-(diphenylmethyl-
silyl)pyrrolidine, which is readily accessible in enantiomeri-
cally pure form by asymmetric synthesis. Its absolute config-
uration was determined by X-ray crystal structure analysis
of the HCl salt. High stereoselectivities and yields have
been achieved in catalyzed enantioselective additions of
propanal and butanal to nitroolefins. These promising re-
sults form the basis for subsequent studies, which have the
goal to introduce new silyl-substituted organocatalysts with
improved properties and to find additional applications of
the current catalyst system.[17]
X-ray analysis by employing Flackꢀs method.[15] (Xabs
À0.036(79) for the structure shown in Figure 1).
=
Experimental Section
Next, (S)-2-(diphenylmethylsilyl)pyrrolidine (3) was ap-
plied in catalytic asymmetric Michael addition reactions of
propanal (4a) and butanal (4b) to nitroolefins (Table 1).
Solvent screening experiments showed that a mixture of tol-
uene/THF (5:1) gave the best results in terms of stereoselec-
tivity and yield (Table 1, entry 1).[14] To our delight, under
the optimized conditions essentially all diastereomeric ratio
(d.r.) and e.r. values were on the >90:x level, and the yields
ranged from 87 to 99%. The only exception was the reac-
tion between propanal and 2-(2-nitrovinyl)furan, which gave
the corresponding product 6i with a lower e.r. (89:11) in a
yield of only 88% (Table 1, entry 9). In general, all reactions
with propanal (4a) were complete within 15–22 h (Table 1,
entries 1–9). Although using butanal (4b) required longer
reaction times (46 and 48 h), the stereoselectivities and
yields were on the same level (Table 1, entries 10 and 11).
General procedure for the Michael addition: A solution of silylated pyr-
rolidine 3 (0.05 mmol) and aldehyde (5.00 mmol) in toluene/THF (5:1,
1.5 mL) was cooled to 08C and stirred for 30 min under an atmosphere
of Ar. Then, the nitroolefin (0.50 mmol) was added and the reaction was
monitored by TLC. When full conversion was indicated, the reaction was
stopped by the addition of a 1m aqueous solution of HCl. The aqueous
layer was extracted with CH2Cl2 (3ꢂ), and the combined organic phases
were dried over MgSO4, filtered, and concentrated in vacuo. After deter-
mination of the diastereomeric ratio by 1H NMR spectroscopy, the prod-
uct was purified by column chromatography. The enantiomeric ratio was
measured by HPLC using a chiral stationary phase. The HPLC condi-
tions and spectral data of all compounds are provided in the Supporting
Information.
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Chem. Eur. J. 2010, 16, 12549 – 12552

Asymmetric Michael Additions
COMMUNICATION
Table 1. Michael addition of aldehydes 4 to nitroolefins 5 catalyzed by
(S)-2-(diphenylmethylsilyl)pyrrolidine (3).[a]
Keywords: asymmetric synthesis
organocatalysis · silicon · silylated pyrrolidines
· Michael addition ·
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17
22
15
19
15
22
22
22
96
93
96
99
96
87
98
93
95:5
95:5
97:3
95:5
92:8
97:3
96:4
96:4
94:6
92:8
92:8
93:7
93:7
93:7
95:5
94:6
2
3
4
5
6
7
8
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22
88
96:4
89:11
10
11
46
48
95
90
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94:6
94:6
95:5
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(0.05 mmol), solvent (1.5 mL), 08C. [b] After column chromatography.
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Acknowledgements
We are grateful to the Fonds der Chemischen Industrie and the Deutsche
Forschungsgemeinschaft (DFG) within the SPP 1179 (ꢃOrganocatalysisꢀ)
for financial support. We also thank Prof. Dr. J. Lambert for valuable
comments on the Si effects.
Chem. Eur. J. 2010, 16, 12549 – 12552
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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9.0303(3) ꢇ,
c=24.9057(8) ꢇ,
V=1679.26(9) ꢇ3,
1calcd =
1.202 MgmÀ3, T=293 K, MoKa, l=0.71073 ꢇ, Vmax =35.38, data col-
lection: Bruker KAPPA APEX II, structure solution: Xtal3.7 (The
Xtal 3.7 System, S. R. Hall, D. J. Du Bolay, R. Olthof-Hazekamp,
University of Western Australia, 2001), refinement on F, R(Rw)=
0.054ACTHNUGRTENUNG(0.040), S=1.571, for 265 parameters and 6144 reflections with
I>2s(I), hydrogen atoms located and refined isotropically, residual
electron density À0.724/0.599 eꢇÀ3. CCDC-778923 contains the sup-
plementary crystallographic data for this structure. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[17] Editorial note: see also closely related paper by C. Strohmann, M.
Christmann, and co-workers: J. O. Bauer, J. Stiller, E. Marquꢄs-
Lꢈpez, K. Strohfeldt, M. Christmann, C. Strohmann, Chem. Eur. J.
2010, DOI: 10.1002/chem.201002166
Received: June 22, 2010
Published online: September 28, 2010
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Chem. Eur. J. 2010, 16, 12549 – 12552