LETTER
Asymmetric Michael Additions of Keto Esters and Diketones to Nitroalkenes
1221
Supporting Information for this article is available online at
Table 4 Variation of 1,3-Dicarbonyl Compound 7 in Reaction with
6a Catalyzed by Thiourea 5ba
O
O
O
O
5b (10 mol%)
Acknowledgment
R1
R3
NO2
+ 6a
R1
R3
Et2O, 0 °C, time
R2
Ph
R2
7a–h
We are grateful to the Fonds der Chemischen Industrie and the
Deutsche Forschungsgemeinschaft (DFG) within the SPP 1179
(‘Organocatalysis’) for financial support, and we thank Dr. I.
Schiffers for stimulating discussions.
9a–h
Entry 1,3-Dicarbonyl
Time
(h)
Yield
ee
(%) (dr)b
(%)c of 9
O
O
O
O
O
O
O
O
References and Notes
1
2
3
4
16
42
17
16
>99
92
(1) For recent reviews on organocatalysis, see:
Me
Ph
Ph
Me
Me
Ph
(a) Enantioselective Organocatalysis; Dalko, P. I., Ed.;
Wiley-VCH: Weinheim, 2007. (b)Berkessel, A.;Gröger, H.
In Asymmetric Organocatalysis; Wiley-VCH: Weinheim,
2005. (c) Dondoni, A.; Massi, A. Angew. Chem. Int. Ed.
2008, 47, 4638; Angew. Chem. 2008, 120, 4716.
67
87
96 (55:45)
92 (55:45)
84 (83)
85 (86)
(d) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38,
2178. (e) Raj, M.; Singh, V. K. Chem. Commun. 2009, 6687.
(2) For reviews on thioureas in catalysis, see: (a) Connon, S. J.
Synlett 2009, 345. (b) Connon, S. J. Chem. Commun. 2008,
2499. (c) Takemoto, Y.; Miyabe, H. Chimia 2007, 61, 269.
(3) For reviews on H-bonding catalysis, see: (a) Schreiner,
P. R. Chem. Soc. Rev. 2003, 32, 289. (b) Wittkopp, A.;
Schreiner, P. R. Chem. Eur. J. 2003, 9, 407. (c) Pihko, P.
M. Angew. Chem. Int. Ed. 2004, 43, 2062; Angew. Chem.
2004, 116, 2110. (d) Taylor, M. S.; Jacobsen, E. N. Angew.
Chem. Int. Ed. 2006, 45, 1520; Angew. Chem. 2006, 118,
1550. (e) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth.
Catal. 2006, 348, 999. (f) Doyle, A. G.; Jacobsen, E. N.
Chem. Rev. 2007, 107, 5713.
OEt
OEt
O
O
5
6
7
18
17
19
>99 (90:10)
>99 (72:28)
98 (94:6)
72 (79)
67 (57)
75 (79)
OMe
O
O
O
Me
O
O
(4) For a recent review on Brønsted bases in organocatalysis,
see: Palomo, C.; Oiarbide, M.; López, R. Chem. Soc. Rev.
2009, 38, 632.
Me
O
O
(5) Selected recent examples: (a) Galzerano, P.; Bencivenni,
G.; Pesciaioli, F.; Mazzanti, A.; Giannichi, B.; Sambri, L.;
Bartoli, G.; Melchiorre, P. Chem. Eur. J. 2009, 15, 7846.
(b) Mei, K.; Jin, M.; Zhang, S.; Li, P.; Liu, W.; Chen, X.;
Xue, F.; Duan, W.; Wang, W. Org. Lett. 2009, 11, 2864.
(c) Yalalov, D. A.; Tsogoeva, S. B.; Shubina, T. E.;
Martynova, I. M.; Clark, T. Angew. Chem. Int. Ed. 2008, 47,
6624; Angew. Chem. 2008, 120, 6726.
(6) For selected recent examples, see: (a) Lu, A.; Gao, P.; Wu,
Y.; Wang, Y.; Zhou, Z.; Tang, C. Org. Biomol. Chem. 2009,
7, 3141. (b) Han, B.; Liu, Q.-P.; Li, R.; Tian, X.; Xiong, X.-
F.; Deng, J.-G.; Chen, Y.-C. Chem. Eur. J. 2008, 14, 8094.
(7) Selected examples: (a) Zuend, S. J.; Jacobsen, E. N. J. Am.
Chem. Soc. 2007, 129, 15872. (b) Inokuma, T.; Hoashi, Y.;
Takemoto, Y. J. Am. Chem. Soc. 2006, 128, 9413.
(8) For recent reviews on asymmetric Michael addition
reactions, see: (a) Almasi, D.; Alonso, D. A.; Nájera, C.
Tetrahedron: Asymmetry 2007, 18, 299. (b) Vicario, J. L.;
Badía, D.; Carrillo, L. Synthesis 2007, 2065. (c) Tsogoeva,
S. B. Eur. J. Org. Chem. 2007, 1701.
(9) For an excellent early overview on asymmetric Michael
additions to nitroalkenes, see: Berner, O. M.; Tedeschi, L.;
Enders, D. Eur. J. Org. Chem. 2002, 1877.
8d
45
53 (83:17)
94 (87)
Me
a The reaction was carried out with 0.2 mmol of 6a and 0.4 mmol of
7 in the presence of 10 mol% of thiourea 5b in 1.0 mL of Et2O.
b Determined by 1H NMR analysis.
c The er were determined by HPLC analysis using a chiral column.
The values in parentheses are the ee values of the minor diastereo-
mers.
d The reaction was conducted at r.t.
(ranging from 72–79% ee for all four diastereomers). In
general, the ee values of the two diastereomeric products
obtained in a given catalysis were similar (Dee 1–10%).
In conclusion, we developed ephedrine- and pseudoephe-
drine-derived thioureas with dimethylamino substituents
and investigated their catalytic properties in Michael ad-
ditions of diketones and b-keto esters to nitroalkenes. The
synthetic approach towards those catalysts is short (three
steps) and provides access to all four stereoisomers start-
ing from cheap, commercially available precursors. Pseu-
doephedrine-derived thiourea 5b showed the best
catalytic performance providing products with up to 94%
ee in good to excellent yields. Subsequent investigations
shall allow a quality assessment of those simple, but novel
thioureas in other asymmetric organocatalyses.
(10) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc.
2003, 125, 12672. (b) Okino, T.; Hoashi, Y.; Furukawa, T.;
Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119.
(11) For selected recent examples, see: (a) Jiang, X.; Zhang, Y.;
Liu, X.; Zhang, G.; Lai, L.; Wu, L.; Zhang, J.; Wang, R.
J. Org. Chem. 2009, 74, 5562. (b) Wang, J.; Li, H.; Duan,
W.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4713. (c) Andrés,
J. M.; Manzano, R.; Pedrosa, R. Chem. Eur. J. 2008, 14,
Synlett 2010, No. 8, 1219–1222 © Thieme Stuttgart · New York