ORGANIC
LETTERS
2006
Vol. 8, No. 26
6099-6102
Highly Enantioselective Michael
Additions of Indole to Benzylidene
Malonate Using Simple Bis(oxazoline)
Ligands: Importance of Metal/Ligand
Ratio
Ramesh Rasappan, Markus Hager, Anja Gissibl, and Oliver Reiser*
Institut fu¨r Organische Chemie, UniVersita¨t Regensburg, UniVersita¨tsstr. 31,
93053 Regensburg, Germany
Received November 5, 2006
ABSTRACT
Simple bis(oxazoline) ligands, especially azabis(oxazolines), can catalyze the copper-catalyzed addition of indoles to benzylidene malonates
in up to >99% ee, provided that excess of chiral ligand is avoided. The paradigm followed in many asymmetric catalyses that an excess of
chiral ligand with respect to the metal should improve enantioselectivity because a background reaction by free metal is suppressed, is not
applicable here, which might call for revisiting some of the many copper(II)−bis(oxazoline)-catalyzed processes known.
Asymmetric Friedel-Crafts alkylations of indoles have been
recently of great interest1 due to the high relevance of indole
derivatives as privileged structures in pharmaceutical drugs.
Among them, the copper-bis(oxazoline)-catalyzed enantio-
selective 1,4-addition of indoles to R,â-unsaturated carbonyl
compounds plays a prominent role, representing a facile,
catalytic asymmetric process for this transformation.2-5 While
in the pioneering work of Jørgensen and co-workers it was
demonstrated that copper(II) complexes with bis(oxazolines)
1a can catalyze the asymmetric addition of indoles to R,â-
unsaturated ketoesters with enantioselectivities of >99% ee,2a
using benzylidene malonates as substrates only proceeded
with moderate selectivities (up to 69% ee) under the same
reaction conditions.2b Subsequently, Tang and co-workers
reported some improvements of the latter reaction with bis-
(oxazoline) ligand 1b (Table 1, entry 2)3 but most importantly
demonstrated in a number of elegant studies that tris-
(oxazoline) ligands such as 3 were superior ligands for this
process, giving the adduct 8a with improved yields and
selectivities up to 93% ee (Table 1, entry 4).4 A pentacoor-
dinated copper(II) complex A was postulated as the decisive
intermediate to account for the high selectivity. In summary,
it was concluded from these studies that bis(oxazolines) are
unsuitable ligands for the title reaction.
(1) Leading review: Bandini, M.; Melloni, A.; Tommasi, S.; Umani-
Ronchi, A. Synlett 2005, 1199.
(2) (a) Jensen, K. B.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2001, 40, 160. (b) Zhuang, W.; Hansen, T.;
Jørgensen, K. A. Chem. Commun. 2001, 347. (c) Yamazaki, S.; Iwata, Y.
J. Org. Chem. 2006, 71, 739.
(3) Zhou, J.; Tang, Y. Chem. Commun. 2004, 432.
(4) (a) Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030. (b). Zhou,
J.; Ye, M.-C.; Huang, Z.-Z.; Tang, Y. J. Org. Chem. 2004, 69, 1309. (c)
Zhou, J.; Ye, M.-C.; Tang, Y. J. Comb. Chem. 2004, 6, 301. (d) Ye, M.-
C.; Li, B.; Zhou, J.; Sun, X.-L.; Tang, Y. J. Org. Chem. 2005, 70, 6108.
(5) (a) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu,
J. J. Am. Chem. Soc. 2003, 125, 10780. (b) Palomo, C.; Oiarbide, M.;
Kardak, B. G.; Garcia, J. M.; Linden, A. J. Am. Chem. Soc. 2005, 127,
4154.
We report here that the ligand/copper ratio is crucial for
the selectivity of the title reaction and that under optimized
reaction conditions conjugate additions with benzylidene
10.1021/ol062697k CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/24/2006