Con tr olla ble En a n tioselective F r ied el-Cr a fts Rea ction 1 betw een
In d oles a n d Alk ylid en e Ma lon a tes Ca ta lyzed by
P seu d o-C3-Sym m etr ic Tr isoxa zolin e Cop p er (II) Com p lexes
J ian Zhou, Meng-Chun Ye, Zheng-Zheng Huang, and Yong Tang*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
tangy@mail.sioc.ac.cn
Received October 20, 2003
Pseudo-C3-symmetric trisoxazoline copper(II) complexes prove to be excellent catalysts in the
Friedel-Crafts alkylation of indoles with alkylidene malonates. The absolute stereochemistry of
this reaction is shown to be dependent on the solvent. Reactions in isobutyl alcohol afford the
Friedel-Crafts alkylation adducts in excellent yields and with up to +98% ee. In 1,1,2,2-
tetrachloroethane (TTCE), however, the opposite enantiomers of the products are obtained in good
yields with up to -89% ee. Water tolerance of chiral catalyst trisoxazoline 2a /Cu(OTf)2 is examined,
and it is found that the addition of up to 200 equiv of water relative to catalyst in isobutyl alcohol
has almost no effect on enantioselectivity but slows down the reaction. The reaction scope is studied
as well. The roles of alcohol as the solvent to accelerate the reaction are discussed. The
stereochemical models of asymmetric induction for reactions both in isobutyl alcohol and in TTCE
are also developed.
In tr od u ction
create superior ligands by varying amino alcohols15 or
bridging substituents.16 In sharp contrast to the great
success of bisoxazolines, the development and applica-
tions of trisoxazolines are very limited.17 In our efforts
to develop superior catalysts which are cheap, easy to
C2-symmetric chiral bisoxazoline-metal complexes are
widely used in asymmetric catalysis.2 For example,
bisoxazoline 1-derived copper complexes have been es-
tablished as versatile catalysts for a series of asymmetric
reactions such as aziridination,3 aldol,4 cycloaddition,5
carbonyl-ene,5e,6 Michael,7 cyclopropanation,8 δ-lactone
formation,9 amination,10 Friedel-Crafts,11 Henry,12 Man-
nich,13 and allylic oxidation reactions.14 Because of the
wide applications of bisoxazolines, much effort has been
devoted to the modification of bisoxazoline framework to
(5) For DA reactions, see: (a) Evans, D. A.; Miller, S. J .; Lectka, T.
J . Am. Chem. Soc. 1993, 115, 6460. (b) Evans, D. A.; J ohnson, J . S. J .
Org. Chem. 1997, 62, 786. (c) Evans, D. A.; Miller, S. J .; Lectka, T.;
von Matt, P. J . Am. Chem. Soc. 1999, 121, 7559. (d) Sibi, M. P.;
Venkatraman, L.; Liu, M.; J asperse, C. P. J . Am. Chem. Soc. 2001,
123, 8444 and references therein. For the HAD reaction, see: (e)
J ohannsen, M.; J ørgensen, K. A. J . Org. Chem. 1995, 60, 5757. (f) Yao,
S.; J ohannsen, M.; Audrain, H.; Hazell, R. G.; J ørgensen, K. A. J . Am.
Chem. Soc. 1998, 120, 8599. (g) Thorhauge, J .; J ohannsen, M.;
J ørgensen, K. A. Angew. Chem., Int. Ed. 1998, 37, 2404. (h) Evans, D.
A.; Olhava, E. J .; J ohnson, J . S.; J aney, J . M. Angew. Chem., Int. Ed.
1998, 37, 3372. (i) Evans, D. A.; J ohnson, J . S. J . Am. Chem. Soc. 1998,
120, 4895. (j) Evans, D. A.; J ohnson, J . S.; Olhava, E. J . J . Am. Chem.
Soc. 2000, 122, 1635. (k) Audrain, H.; Thorhauge, J .; Hazell, R. G.;
J ørgensen, K. A. J . Org. Chem. 2000, 65, 4487 and references therein.
For cycloadditions of silyl ketenes, see: (l) Evans, D. A.; J aney, J . M.
Org. Lett. 2001, 3, 2125.
(6) (a) Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.;
Tregay, S. W. J . Am. Chem. Soc. 1998, 120, 5824. (b) Reichel, F.; Fang,
X.; Yao, S.; Ricci, M.; J ørgensen, K. A. Chem. Commun. 1999, 1505.
(c) Gathergood, N.; J ørgensen, K. A. Chem. Commun. 1999, 1869. (d)
Evans, D. A.; Tregay, S. W.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.
J . Am. Chem. Soc. 2000, 122, 7936. (e) Gao, Y.; Lane-Bell, P.; Vederas,
J . C. J . Org. Chem. 1998, 63, 2133.
* Corresponding author.
(1) This reaction can also be viewed as a Michael addition reaction,
but the majority of literatures regarded such a reaction as a Friedel-
Crafts reaction, please see refs 11b, 11c, 20 and: (a) Paras, N. A.;
MacMillan, D. W. C. J . Am. Chem. Soc. 2001, 123, 4370. (b) Bolm, C.;
Hildebrand, J . P.; Mun˜iz, K.; Hermanns, N. Angew. Chem., Int. Ed.
2001, 40, 3285. (c) J ørgensen, K. A. Synthesis 2003, 1117. For Michael
addition, please see a recent review: (d) Krause, N.; Hoffmann-Ro¨der,
A. Synthesis 2001, 171.
(2) (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J . Tetrahedron:
Asymmetry 1998, 9, 1. (b) Evans, D. A.; Rovis, T.; J ohnson, J . S. Pure
Appl. Chem. 1999, 71, 1407. (c) J ørgensen, K. A.; J ohannsen, M.; Yao,
S.; Audrain, H.; Thorhauge, J . Acc. Chem. Res. 1999, 32, 605. (d)
J ohnson, J . S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325. (e)
J ørgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3559.
(3) (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.;
Barnes, D. M. J . Am. Chem. Soc. 1993, 115, 5328. (b) Hansen, K. B.;
Finney, N. S.; J acobsen, E. N. Angew. Chem., Int. Ed. Engl. 1995, 34,
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(4) (a) Evans, D. A.; Murry, J . A.; Kozlowski, M. C. J . Am. Chem.
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10.1021/jo035552p CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/16/2004
J . Org. Chem. 2004, 69, 1309-1320
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