Importance of chiral phase-transfer catalysts with dual functions in obtaining high enantioselectivity in the Michael reaction of malonates and chalcone derivatives

Article abstract of DOI:10.1021/ol050902a

(Chemical Equation Presented) Highly enantioselective Michael addition of diethyl malonate to chalcone derivatives has been achieved under mild phase-transfer conditions by the successful utilization of N-spiro C ₂-symmetric chiral quaternary a

Full text of DOI:10.1021/ol050902a

ORGANIC
LETTERS
2
005
Vol. 7, No. 15
195-3197
Importance of Chiral Phase-Transfer
Catalysts with Dual Functions in
Obtaining High Enantioselectivity in the
Michael Reaction of Malonates and
Chalcone Derivatives
3
Takashi Ooi, Daisuke Ohara, Kazuhiro Fukumoto, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo,
Kyoto 606-8502, Japan
maruoka@kuchem.kyoto-u.ac.jp
Received April 22, 2005
ABSTRACT
Highly enantioselective Michael addition of diethyl malonate to chalcone derivatives has been achieved under mild phase-transfer conditions
by the successful utilization of N-spiro C -symmetric chiral quaternary ammonium bromide 1 as a catalyst, which possesses diarylhydroxymethyl
2
functionalities as a recognition site for the prochiral electrophile. This simple asymmetric Michael addition process was found to be quite
effective for various chalcone derivatives, including those with heteroaromatic substituents.
d-g
During the past decade, the development of asymmetric
phase-transfer catalysis based on the use of structurally well-
defined chiral, nonracemic catalysts has resulted in notable
achievements, making it feasible to perform various bond
formation reactions under mild phase-transfer-catalyzed
ization of glycinate Schiff bases.1 This, in turn, indicates
the difficulty of controlling the stereochemical outcome of
the additions of nucleophiles lacking prochirality to prochiral
electrophiles, on which new stereogenic centers are solely
created. Indeed, synthetically useful reactions of this type
1
1a-c
conditions. The characteristic aspect of this success is that
have been relatively restricted
and the enantioselective
most of the highly stereoselective transformations involve
prochiral nucleophiles (enolates) pairing with chiral onium
cations, as well-exemplified by the asymmetric functional-
oxidation of R,â-unsaturated ketones represents such rare
2-4,7
examples.
The asymmetric carbon-carbon bond forma-
tion through the Michael addition of malonates to chalcone
(
1) For recent reviews, see: (a) Shioiri, T. In Handbook of Phase-Transfer
(2) Recent representative examples of phase-transfer-catalyzed asym-
metric epoxidation: (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1998,
39, 1599. (b) Corey, E. J.; Zhang, F.-Y. Org. Lett. 1999, 1, 1287. (c) Lygo,
B.; To, D. C. M. Tetrahedron Lett. 2001, 42, 1343. (d) Adam, W.; Rao, P.
B.; Degen, H.-G.; L e´ vai, A.; Patonay, T.; SahaM o¨ ller, C. R. J. Org. Chem.
2002, 67, 259. (e) Arai, S.; Tsuge, H.; Oku, M.; Miura, M.; Shioiri, T.
Tetrahedron 2002, 58, 1623. (f) Ye, J.; Wang, Y.; Liu, R.; Zhang, G.; Zhang,
Q.; Chen, J.; Liang, X. Chem. Commun. 2003, 2714. (g) Allingham, M. T.;
Howard-Jones, A.; Murphy, P. J.; Thomas, D. A.; Caulkett, P. W. R.
Tetrahedron Lett. 2003, 44, 8677. (h) Bak o´ , T.; Bak o´ , P.; Keglevich, G.;
Catalysis; Sasson, Y., Neumann, R., Eds.; Blackie Academic & Profes-
sional: London, 1997; Chapter 14. (b) Shioiri T.; Arai, S. In Stimulating
Concepts in Chemistry, Vogtle, F., Stoddart, J. F., Shibasaki, M., Eds.;
Wiley-VCH: Weinheim, 2000; p 123. (c) O’Donnell, M. J. In Catalytic
Asymmetric Syntheses, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York,
2
000; Chapter 10. (d) O’Donnell, M. J. Aldrichimica Acta 2001, 34, 3. (e)
Maruoka, K.; Ooi, T. Chem. ReV. 2003, 103, 3013. (f) O’Donnell, M. J.
Acc. Chem. Res. 2004, 37, 506. (g) Lygo, B.; Andrews, B. I. Acc. Chem.
Res. 2004, 37, 518.
1
0.1021/ol050902a CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/28/2005

derivatives also belongs to this category, but only a few
reports have appeared in the literature with limited success.
turned out to be quite promising (84% ee) (entry 1 in Table
1). This result prompted us to examine the effect of the
5,6
8
In conjunction with our recent effort toward finding a general
solution to this intrinsic problem by the rational molecular
design of dual-functioning chiral phase-transfer catalysts of
type 1, we have been interested in evaluating the effective-
ness of our approach in the Michael reaction of malonates
and chalcones (Scheme 1). In this letter, we wish to describe
Table 1. Effect of the Ester Substituent (R′) on the Reactivity
and Stereoselectivity in the Catalytic Asymmetric Michael
Addition of Dialkyl Malonate to Chalcone (3a) under
Phase-Transfer Conditionsa
7
Scheme 1
% yieldb
% ee (configuration)d
c
entry
catalyst
R′
1
2
3
4
5
6
7
1
1
1
1
1
1
2
Me
Et
Et
Bn
i-Pr
t-Bu
Et
99
99
99
99
99
84
86 (R)
90 (R)
61
e
74
f
nr
98
15 (R)
a
Unless otherwise specified, the reaction was conducted with 4 equiv
of dialkyl malonate in the presence of 3 mol % of 1 or 2 and 10 mol % of
K2CO3 in toluene at 0 °C for 24 h. b Isolated yield. c Enantiopurity of the
Michael adduct 4a was determined by HPLC analysis using a chiral column
d
(
DAICEL Chiralpak AD-H) with hexane-ethanol as a solvent. Absolute
configuration was determined by comparison of the optical rotation with
the value previously reported.11 Performed at -20 °C. No reaction.
e
f
the preliminary results of this study, demonstrating the
importance of the chiral catalyst with a recognition site for
the electrophile to control the absolute stereochemistry of
the chiral carbon center generated on the prochiral chalcone
derivatives.
ester substituent (R′) of malonates, which revealed that
diethyl malonate appeared to be an optimal Michael donor
in terms of both reactivity and selectivity (entry 2). The
enantioselectivity reached 90% ee upon performing the
addition at lower temperature (-20 °C) (entry 3). On the
other hand, the reaction with dibenzyl malonate resulted in
a substantial decrease in the stereoselectivity, in contrast to
the previous report (entry 4), and no indication of the
product formation was observed when di-tert-butyl malonate
was employed (entry 6). Here, it is particularly emphasized
that the control reaction with diethyl malonate by the use of
catalyst 2 under otherwise identical conditions brought a
significant loss of enantiomeric excess (entry 7), indicating
the crucial importance of the hydroxy functionality for the
adequate enantiofacial differentiation of the prochiral chal-
cone.
We initiated this research program by examining the
applicability of chiral quaternary ammonium bromide 1, a
promising catalyst for the asymmetric epoxidation of R,â-
7
unsaturated ketones, to the addition of dimethyl malonate
5
a
to chalcone (3a). Thus, a mixture of chalcone, dimethyl
malonate, 1 (3 mol %), and potassium carbonate (K
2 3
CO )
(10 mol %) in toluene was vigorously stirred at 0 °C, and
after 24 h, the desired Michael adduct 4a (R′ ) Me) was
isolated quantitatively. Fortunately, its enantiomeric excess
Bombicz, P.; Kubinyi, M.; P a´ l, K.; Bodor, S.; Mak o´ , A.; T o˜ ke, L.
Tetrahedron: Asymmetry 2004, 15, 1589. (i) Jew, S.-s.; Lee, J.-H.; Jeong,
B.-S.; Yoo, M.-S.; Kim, M.-J.; Lee, Y.-J.; Lee, J.; Choi, S.-h.; Lee, K.;
Lah, M. S.; Park, H.-g. Angew. Chem., Int. Ed. 2005, 44, 1383.
(3) Asymmetric dihydroxylation: Bhunnoo, R. A.; Hu, Y.; Lain e´ , D. I.;
With this information in hand, we next pursued experi-
Brown, R. C. D. Angew. Chem., Int. Ed. 2002, 41, 3479. See also: Brown,
R. C. D.; Keily, J. F. Angew. Chem., Int. Ed. 2001, 40, 4496.
9
ments to probe the scope of the 1,4-diarylenone 3. As listed
(4) For other contributions, see, for example: (a) Asymmetric Michael
in Table 2, the present phase-transfer-catalyzed Michael
addition of diethyl malonate in the presence of catalyst 1 (3
mol %) and K CO (10 mol %) in toluene tolerated both
2 3
electron-withdrawing and -donating groups on the aryl
substituents, and thus the corresponding Michael adducts
addition of 2-nitropropane: Bak o´ , P.; Czinege, E.; Bak o´ , T.; Czugler, M.;
T o˜ ke, L. Tetrahedron: Asymmetry 1999, 10, 4539. (b) Asymmetric
cyclopropanation: Arai, S.; Nakayama, K.; Ishida, T.; Shioiri, T. Tetra-
hedron Lett. 1999, 40, 4215. (c) Asymmetric aldol reaction: Arai, S.;
Hasegawa, K.; Nishida, A. Tetrahedron Lett. 2004, 45, 1023. See also ref
1
c.
(
5) (a) Kim, D. Y.; Huh, S. C.; Kim, S. M. Tetrahedron Lett. 2001, 42,
6
299. (b) Dere, R. T.; Pal, R. R.; Patil, P. S.; Salunkhe, M. M. Tetrahedron
Lett. 2003, 44, 5351. See also: (c) Loupy, A.; Zaparucha, A. Tetrahedron
Lett. 1993, 34, 473.
(8) The following results of the evaluation of the catalyst structure in
the addition of dimethyl malonate to chalcone revealed the superiority of 1
(Ar ) R ) 3,5-Ph2-C6H3): 56% ee (Ar ) Ph, R ) H); 72% ee (Ar )
4-CF3-C6H4, R ) H); 33% ee (Ar ) 3,5-(CF3)2-C6H3, R ) H); 50% ee
(Ar ) 3,5-(MeO)2-C6H3, R ) H); 76% ee (Ar ) 3,5-Ph2-C6H3, R ) H).
(9) Present method could not be extended well to aliphatic enones. For
example, the reaction of diethyl malonate with trans-4-phenyl-3-buten-2-
one under the influence of 1 proceeded slowly at 0 °C to furnish the desired
Michael adduct in 98% yield with 8% ee after 96 h.
(6) For the asymmetric Michael addition of malonates to chalcone
catalyzed by chiral metal complexes, see: (a) Sasai, H.; Arai, T.; Satow,
Y.; Houk, K. N.; Shibasaki, M. J. Am. Chem. Soc. 1995, 117, 6194. (b)
Kumaraswamy, G.; Sastry, M. N. V.; Jena, N. Tetrahedron Lett. 2001, 42,
8
515.
(7) Ooi, T.; Ohara, D.; Tamura, M.; Maruoka, K. J. Am. Chem. Soc.
2
004, 126, 6844.
3196
Org. Lett., Vol. 7, No. 15, 2005

Finally, we found that dialkyl malonate was not a uniquely
effective Michael donor. For instance, malononitrile under-
went smooth and highly enantioselective addition to chalcone
catalyzed by 1 under similar phase-transfer conditions,
affording the corresponding Michael adduct 5 in 98% yield
Table 2. Catalytic Asymmetric Michael Addition of Diethyl
Malonate to Chalcone Derivatives 3 under Phase-Transfer
Conditionsa
1
0
with 81% ee as shown in Scheme 2.
Scheme 2
In summary, we have demonstrated that uniformly high
enantioselectivity can be attained in the Michael reaction of
diethyl malonate and various chalcone derivatives using a
chiral phase-transfer catalyst with dual functions. This
Michael addition chemistry also accommodates malononitrile
as a nucleophile. The present study further underscores the
effectiveness of our strategy based on the design of new
chiral phase-transfer catalysts equipped with an appropriate
recognition site for a requisite prochiral electrophile.
Acknowledgment. This work was partially supported by
the Kurata Memorial Hitachi Science and Technology
Foundation, the Asahi Glass Foundation, and a Grant-in-
Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
a
Unless otherwise noted, the reaction was carried out with 4 equiv of
diethyl malonate in the presence of 3 mol % of 1 and 10 mol % of K2CO3
b
c
in toluene at -20 °C for 24 h. Isolated yield. Enantiopurity of products
was determined by HPLC analysis using a chiral column with hexane-
Supporting Information Available: General experimen-
tal procedure and spectroscopic characterization of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
d
ethanol as a solvent. For detail, see Supporting Information. Stirring for
e
4
8 h. At -30 °C for 48 h.
were obtained in excellent chemical yields with a high level
of enantiomeric excesses (entries 1-5). Notably, high
enantioselectivity was also observed in the reaction with the
substrates incorporating heteroaromatic substituents either on
the double bond or on the carbonyl carbon, expanding the
utility of this method as a practical tool for accessing a variety
of useful synthetic building blocks of high optical purities
OL050902A
(
10) For catalytic asymmetric Michael addition of malononitrile to R,â-
unsaturated ketones, see: (a) Taylor, M. S.; Zalatan, D. N.; Lerchner, A.
M.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 1313. For related studies,
see: (b) Itoh, K.; Oderaotoshi, Y.; Kanemasa, S. Tetrahedron: Asymmetry
2
003, 14, 635. (c) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003,
125, 11204.
(entries 6-9).
(11) Yasuda, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1996, 37, 6343.
Org. Lett., Vol. 7, No. 15, 2005
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