C3-symmetric chiral Trisimidazoline: Design and application to organocatalyst

Article abstract of DOI:10.1021/ol902958m

(Figure Presented) C₃-symmetric chlral trislmidazoline was designed and synthesized as a new entry of organocatalyst with the concept of constructing C₃symmetric molecules with three C₂-symmetric chiral components, and the application of this novel catalyst to asymmetric conjugate addition of β-ketoesters to nitroolefins was described.

Full text of DOI:10.1021/ol902958m

ORGANIC
LETTERS
2010
Vol. 12, No. 5
964-966
C3-Symmetric Chiral Trisimidazoline:
Design and Application to Organocatalyst
Kenichi Murai, Shunsuke Fukushima, Shoko Hayashi, Yusuke Takahara, and
Hiromichi Fujioka*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity, 1-6 Yamada-oka,
Suita, Osaka, 565-0871 Japan
fujioka@phs.osaka-u.ac.jp
Received December 25, 2009
ABSTRACT
C3-symmetric chiral trisimidazoline was designed and synthesized as a new entry of organocatalyst with the concept of constructing C3-
symmetric molecules with three C2-symmetric chiral components, and the application of this novel catalyst to asymmetric conjugate addition
of ꢀ-ketoesters to nitroolefins was described.
One of the key challenges in organic chemistry is to design
and develop a new catalyst scaffold.1 Imidazolines are
structural analogues of oxazolines, which are one of the
widely used structures for chiral ligands,2 and various
substituents can be introduced on the nitrogen atom for tuning
the steric environment and electron density. Therefore, their
use as chiral ligands has recently been developed.3 Mean-
while, their use as organocatalysts has not been significantly
explored, though they have great potential due to their basicity,
nucleophilicity, and the Brønsted acidity of their salts (Figure
1i).4 There are only a few asymmetric reactions with
imidazolines as an organocatalyst such as the Diels-Alder
reactions (as acid catalysts)4a,b and the Morita Baylis-Hillman
(1) ComprehensiVe Asymmetric Catalysis; Jacobsenm, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer-Verlag: Heidelberg: Germany, 1999; Vols.
Figure 1. Design of the catalyst.
1-3.
(2) Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. ReV. 2006, 106,
3561.
(3) Liu, H.; Du, D.-M. AdV. Synth. Catal. 2009, 351, 489.
reactions (as nucleophilic base catalysts).4c However, no high
enantioselectivity has been achieved. In addition, despite the
fact that there has been much attention regarding C3-symmetric
molecules in the area of molecular recognition, chiral ligands,
and material science,5,6 applications to organocatalysts are
rare.7 We now report the first highly enantioselective reaction
(4) (a) Tsogoeva, S. B.; Du¨rner, G.; Bolte, M.; Go¨bel, M. W. Eur. J.
Org. Chem. 2003, 1661. (b) Akalay, D.; Du¨rner, G.; Bats, J. W.; Bolte,
M.; Go¨bel, M. W. J. Org. Chem. 2007, 72, 5618. (c) Xu, J.; Guan, Y.;
Yang, S.; Ng, Y.; Peh, G.; Tan, C.-H. Chem. Asian J. 2006, 1, 724. (d)
Weatherwax, A.; Abraham, C. J.; Lectka, T. Org. Lett. 2005, 7, 3461. (e)
Annamalai, V. R.; Linton, E. C.; Kozlowski, M. C. Org. Lett. 2009, 11,
621.
10.1021/ol902958m  2010 American Chemical Society
Published on Web 02/04/2010

using imidazolines as an organocatalyst, i.e., the newly
designed C3-symmetric chiral trisimidazoline 1a (Figure 1ii),
with the concept of constructing C3-symmetric molecules
with three C2-symmetric chiral components, as a Brønsted
base catalyst8 for the enantioselective conjugate addition of
R-substituted ꢀ-ketoesters to nitroolefins.
Table 1. Evaluation of the Imidazolines 1a-ca
Imidazolines derived from C2-symmetric diamines, such as
chiral 1,2-diphenyl ethylenediamine, have a symmetrical struc-
ture. To utilize the symmetric nature of imidazolines, we
designed the C3-symmetric trisimidazoline 1a (Figure 1ii): three-
imidazoline rings were substituted on the 1-, 3-, and 5-positions
of the benzene ring. Since the interesting molecular recognition
of trisimidazoline derived from ethylenediamine was reported
to form 1:3 complexes with carboxylic acids or tetrazoles,9 we
expected that 1a would have good interactions between the
reaction substrates and provide a unique chiral environment.
We chose the ꢀ-ketoester as a substrate assuming that the
enolate of the ꢀ-ketoester and trisimidazoline 1a could form a
complex through hydrogen-bonding interactions. The conjugate
addition of R-substituted ꢀ-ketoesters to nitroolefins was initially
studied, because this reaction is very attractive from the point of
constructing quaternary and tertiary stereocenters in one step.10,11
The C3-symmetric trisimidazoline 1a was readily prepared
by a one-pot condensation-oxidation procedure developed
by us12 from trialdehyde 2 and chiral diamine 3 with NBS
(Scheme 1). In the same way, bisimidazoline 1b and
monoimidazoline 1c were also prepared for comparison.
entry
cat.
loading (mol %) yield (%) (dr) ee (%)b
1
2
3
1a (tris)
1b (bis)
1c (mono)
1a (tris)
1b (bis)
1a (tris)
5
5
5
94 (18:1)
91 (18:1)
29 (5:1)
89
61
1
4
2.5
7.5
5
97 (18:1)
90 (16:1)
95 (20:1)
90
67
95
5
6c
a Unless otherwise noted, the reaction was carried out with 4 (0.14 mmol)
and 5 (0.21 mmol) with 1 in toluene (0.47 mL) at rt. b Ee of major
diastereomer is shown. c -10 °C.
delight, the C3-symmetric trisimidazoline 1a had a good
enantioselectivity (entry 1, 89% ee). A moderate selectivity
was obtained with bisimidazoline 1b (entry 2, 61% ee), while
monoimidazoline 1c produced an almost racemic product
(entry 3, 1% ee). The reduction of the loading of 1a and the
increase of 1b did not have significant influence on the
selectivity: 2.5 mol % of 1a afforded 6a in 90% ee (entry 4)
and 7.5 mol % of 1b afforded 6a in 67% ee (entry 5). These
results indicated that at least two imidazolines on the benzene
ring were essential for this reaction and the structure of
trisimidazoline 1a was much more effective than that of
bisimidazoline 1b. Encouraged by these results, we screened
several solvents to optimize the conditions using 1a. Details
are shown in the Supporting Information, and less polar solvents
tended to produce a good enantioselectivity but a protic solvent,
such as MeOH, resulted in a poor selectivity (4% ee). After
the optimization, lowering the reaction temperature to -10 °C
led to a further improvement of the enantioselectivity (entry 6,
95% ee) with high diastereoselectivity.
Scheme 1. Preparation of Trisimidazoline 1a (left) and
Structures of Bisimidazoline 1b and Monoimidazoline 1c (right)
With the optimized reaction conditions in hand, the
generality of the reactions using the several nitroolefins and
ꢀ-ketoesters was investigated (Table 2). The reaction of
ꢀ-ketoester 4a with different substituted aromatic nitroolefins,
such as electron-rich, electron-poor, bulky, and heteroaro-
matic ones, afforded the corresponding adducts in good yields
with high diastereo- and enantioselectivities (entries 1-7).
The reaction of methyl 2-oxocyclopentanecarboxylate (4a)
and ꢀ-nitrostyrene (5a) was examined to evaluate the
imidazoline catalysts 1a-c (5 mol %) (Table 1). To our
(5) For reviews, see: (a) Moberg, C. Angew. Chem., Int. Ed. 1998, 37,
248. (b) Gibson, S. E.; Castaldi, M. P. Angew. Chem., Int. Ed. 2006, 45,
4718. (c) Moberg, C. Angew. Chem., Int. Ed. 2006, 45, 4721. (d) Gibson,
S. E.; Castaldi, M. P. Chem. Commun. 2006, 3045.
(10) For selected reviews on asymmetric 1,4-addition, see: (a) Tsogoeva,
S. B. Eur. J. Org. Chem. 2007, 1701. (b) Christoffers, J.; Koripelly, G.;
Rosiak, A.; Ro¨ssle, M. Synthesis 2007, 1279.
(11) For selected recent examples with organocatalysts, see: (a) Li, H.;
Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L.
Angew. Chem., Int. Ed. 2005, 44, 105. (b) Okino, T.; Hoashi, Y.; Furukawa,
T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119. (c) Terada,
M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454. (d) Zhang,
Z.-H.; Dong, X.-Q.; Chen, D.; Wang, C.-J. Chem.sEur. J. 2008, 14, 8780.
(e) Yu, Z.; Liu, X.; Zhou, L.; Lin, L.; Feng, X. Angew. Chem., Int. Ed.
2009, 48, 5195. (f) Luo, J.; Xu, L.-W.; Hay, R. A. S.; Lu, Y. Org. Lett.
2009, 11, 437. (g) Jiang, X.; Zhang, Y.; Liu, X.; Zhang, G.; Lai, L.; Wu,
L.; Zhang, J.; Wang, R. J. Org. Chem. 2009, 74, 5562.
(6) Interesting molecular recognitions and chiral ligands with C3-
symmetric trisoxazolines were reported. For examples, see: (a) Kim, S.-
G.; Kim, K.-H.; Jung, J.; Shin, S. K.; Ahn, K. H. J. Am. Chem. Soc. 2002,
124, 591. (b) Ahn, K. H.; Ku, H.-Y.; Kim, Y.; Kim, S.-G.; Kim, Y. K.;
Son, H. S.; Ku, J. K. Org. Lett. 2003, 5, 1419. (c) Gade, L. H.; Bellemin-
Laponnaz, S. Chem.sEur. J. 2008, 14, 4142.
(7) Han, J.; Wu, H.; Teng, M.; Li, Z.; Wang, Y.; Wang, L.; Pan, Y.
Synlett 2009, 933.
(8) Palomo, C.; Oiarbide, M.; Lo´pez, R. Chem. Soc. ReV. 2009, 38, 632.
(9) (a) Kraft, A.; Fro¨hlich, R. Chem. Commun. 1998, 1085. (b) Kraft,
A.; Osterod, F.; Fro¨hlich, R. J. Org. Chem. 1999, 64, 6425. For another
interesting propery of trisimidazolines, see: (c) Nam, S. R.; Kim, H.-J.;
Sakamoto, S.; Yamaguchi, K.; Hong, J.-I. Tetrahedron Lett. 2004, 45, 1339–
1342. (d) Yan, L.; Wang, Z.; Chen, M.-T.; Wu, N.; Lan, J.; Gao, X.; You,
J.; Gau, H.-M.; Chen, C.-T. Chem.sEur. J. 2008, 14, 11601–11609.
(12) (a) Fujioka, H.; Murai, K.; Ohba, Y.; Hiramatsu, A.; Kita, Y.
Tetrahedron Lett. 2005, 46, 2197. (b) Fujioka, H.; Murai, K.; Kubo, O.;
Ohba, Y.; Kita, Y. Tetrahedron 2007, 63, 638. For our related works, see:
(c) Murai, K.; Morishita, M.; Nakatani, R.; Kubo, O.; Fujioka, H.; Kita, Y.
J. Org. Chem. 2007, 72, 8947. (d) Murai, K.; Morishita, M.; Nakatani, R.;
Fujioka, H.; Kita, Y. Chem. Commun. 2008, 4498.
Org. Lett., Vol. 12, No. 5, 2010
965

imidazolines to discriminate the enantiotopic face of the enolate
and (ii) the ꢀ-ketoester and nitroolefin could be activated by
one imidazoline, respectively. In both models, one imidazoline
(ring a, Figure 2) should work as a Brønsted base and another
imidazoline (ring b, Figure 2) as a proton donor. The importance
of the hydrogen atom on the nitrogen of 1a was supported by
the low selectivity of the reaction in MeOH and the control
experiment with N-Me trisimidazoline 1d (Scheme 2); the
reaction of 4a and 5a with 1d afforded 6a in 26% ee and the
reaction with 1d was much slower than that with 1a.13
Table 2. Generalitya
Scheme 2. Control Experiment with N-Me Trisimidazoline 1d
The beneficial effect of the C3-symmetry of 1a was
assumed to create three equally aligned reaction sites
surrounded by two imidazolines providing a better chiral
environment. On the other hand, in the case of bisimidazoline
1b, the reaction could proceed in a space outside of the
possible reaction site surrounded by two imidazolines and
be catalyzed by one of the two imidazolines, though the
details need to be investigated.
In summary, we have designed the C3-symmetric trisimi-
dazoline 1a as a new organocatalyst, and demonstrated that
it catalyzes the asymmetric conjugate addition of ꢀ-ketoesters
to nitroolefins. This is the first highly enantioselective
reaction with imidazolines as organocatalyst. The superiority
of the C3-symmetric structure on the imidazoline catalyst
was also demonstrated. The efficiency as an organocatalyst
could be regarded as one of the new functionalities of C3-
symmetric molecules and the design principle constructing
C3-symmetric molecules with three C2-symmetric chiral
components could be applicable to other organocatalysts.
Additional investigations to clarify the mechanism and its
applications to other reactions are currently underway.
a Unless otherwise noted, the reaction was carried out with 4 (0.14 mmol)
and 5 (0.21 mmol) with 1a (0.007 mmol) in toluene (0.47 mL) at -10 °C.
b 0 °C. c 10 mol % of 1a, rt. d Ee of major diastereomer is shown. e Absolute
and relative configurations were not determined. f Absolute configuration
was not determined.
The indanone carboxylate 4b and tetralone carboxylate 4c
were also applicable (entries 8 and 9). Most of the products
6 were reported compounds and proposed stereochemistries
in the literature11b,d were shown as the scheme in Table 2.
On the basis of the results of the reaction with trisimidazoline
1a, bisimidazoline 1b, or monoimidazoline 1c (see, Table 1,
entries 1-3), two imidazolines on the benzene ring were
involved in the enantioselective addition. Since imidazolines
would work as Brønsted bases, they could activate the ꢀ-ke-
toesters. Once the imidazolines were protonated, they could
work as proton donors. Therefore, we assume that the following
two activation models i and ii are possible (Figure 2): (i) the
ꢀ-ketoester could be activated through interactions with the two
Acknowledgment. This work was financially supported
by a Grant-in-Aid for Scientific Research (B) and for Young
Scientists (B).
Supporting Information Available: Experimental details
and detailed spectroscopic data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL902958M
(13) When 1a was used, the reaction time was 48 h (Table 1, entry 1),
while when 1d was used, the reaction was not completed and stopped in
54 h.
Figure 2. Possible transition states.
966
Org. Lett., Vol. 12, No. 5, 2010