ORGANIC
LETTERS
2012
Vol. 14, No. 17
4518–4521
Asymmetric Michael Additions
of r‑Nitrocyclohexanone to Aryl
Nitroalkenes Catalyzed by Natural Amino
Acid-Derived Bifunctional Thioureas
€
Manuel Jorres, Ingo Schiffers, Iuliana Atodiresei, and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg1,
D-52074 Aachen, Germany
Received July 19, 2012
ABSTRACT
A series of new thiourea catalysts prepared from natural amino acids have been applied in organocatalytic asymmetric Michael additions of
R-nitrocyclohexanone to nitroalkenes. The resulting addition products are formed with excellent enantioselectivities (up to an er of 98:2) in good
yields (up to 90%).
Organocatalysis has become a well-respected methodol-
ogy in asymmetric organic synthesis.1,2 Besides activation
via enamines or imminium ions, hydrogen bonding plays a
major role.3 Catalysts combining both a hydrogen donor
and a hydrogen acceptor are of particular interest because
they allow a simultaneous activation of two reactants.4
Excellent examples include the thioureas by Takemoto5
and Jacobsen,6 in which the H-binding cores are combined
with (di)amino-based H-acceptors.7
Initially, our work wasfocused ontheuseofbifunctional
thioureas in the enantioselective desymmetrization of
meso-anhydrides.8 Further interest in this catalyst type
(1) For recent books, see: (a) Enantioselective Organocatalysis;
Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007. (b) Organocatalysis; Reetz,
M. T., List, B., Jaroch, S., Weinmann, H., Eds.; Springer: Berlin, 2008.
(2) For selected recent reviews on organocatalysis, see: (a) Mukherjee,
S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. (b)
(6) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.
ꢀ
(7) For other examples, see: (a) Vakulya, B.; Varga, S.; Csampai, A.;
ꢀ
Soos, T. Org. Lett. 2005, 7, 1967. (b) McCooey, S. H.; Connon, S. J.
€
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Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed. 2007,
Angew. Chem., Int. Ed. 2005, 44, 6367. (c) Andres, J. M.; Manzano, R.;
46, 1570. (c) MacMillan, D. W. C. Nature 2008, 455, 304. (d) Dondoni,
A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638. (e) Melchiorre, P.;
Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47,
6138. (f) Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516. (g) Bertelsen, S.;
Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178. (h) Pihko, P. M.;
Pedrosa, R. Chem.;Eur. J. 2008, 14, 5116. (d) Ma, Z.-W.; Liu, Y.-X.;
Huo, L.-J.; Gao, X.; Tao, J.-C. Tetrahedron: Asymmetry 2012, 23, 443.
(8) Schmitt, E.; Schiffers, I.; Bolm, C. Tetrahedron 2010, 66, 6349.
(9) Flock, A. M.; Krebs, A.; Bolm, C. Synlett 2010, 1219.
(10) For other recent examples of thiourea-catalyzed Michael addi-
tion reactions, see: (a) Cao, Y.; Jiang, X.; Liu, L.; Shen, F.; Zhang, F.;
Wang, R. Angew. Chem., Int. Ed. 2011, 50, 9124. (b) Dong, X.-Q.; Fang,
X.; Wang, C.-J. Org. Lett. 2011, 13, 4426. (c) Ramireddy, N.; Abbaraju,
S.; Zhao, C.-G. Tetrahedron Lett. 2011, 52, 6792. (d) Rana, N. K.; Singh,
V. K. Org. Lett. 2011, 13, 6520. (e) Bai, J.-F.; Wang, L.-L.; Peng, L.;
Guo, Y.-L.; Jia, L.-N.; Tian, F.; He, G.-Y.; Xu, X.-Y.; Wang, L.-X.
J. Org. Chem. 2012, 77, 2947. (f) Urbanietz, G.; Cassens-Sasse, E.; Keeß,
S.; Raabe, G.; Enders, D. Adv. Synth. Catal. 2012, 354, 1481. (g) Parra,
€
Majander, I.; Erkkila, A. Top. Curr. Chem. 2010, 291, 29.
(3) For reviews on hydrogen-bonding catalysis, see: (a) Schreiner,
P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217. (b) Schreiner, P. R. Chem.
Soc. Rev. 2003, 32, 289. (c) Pihko, P. M. Angew. Chem., Int. Ed. 2004, 43,
2062. (d) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713.
(e) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187.
(4) For reviews on bifunctional hydrogen-bonding catalysis, see:
(a) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299. (b) Taylor, M. S.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (c) Connon, S. J.
Chem. Commun. 2008, 2499. (d) Connon, S. J. Synlett 2009, 354. (e) Lu,
L.-Q.; An, X.-L.; Chen, J.-R.; Xiao, W.-J. Synlett 2012, 23, 490.
(5) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003,
125, 12672.
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A.; Uria, U.; Besselievre, F.; Merino, E.; Rueping, M. Org. Lett. 2010,
12, 5680. (h) Raimondi, W.; Basl, O.; Constantieux, T.; Bonne, D.;
Rodriguez, J. Adv. Synth. Catal. 2012, 354, 563. (i) Li, X.; Zhang, Y.-Y.;
Xue, X.-S.; Jin, J.-L.; Tan, B.-X.; Liu, C.; Dong, N.; Cheng, J.-P. Eur. J.
Org. Chem. 2012, 1774.
r
10.1021/ol302005f
Published on Web 08/28/2012
2012 American Chemical Society